Compositions useful as inhibitors of voltage-gated sodium channels

ABSTRACT

The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. applicationSer. No. 10/914,988, filed Aug. 9, 2004, which claims the benefit ofU.S. Provisional patent application No. 60/493,659, filed Aug. 8, 2003,and U.S. Provisional patent application No. 60/584,717, filed Jul. 1,2004, the entire contents of these three applications being incorporatedherein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofvoltage-gated sodium channels and calcium channels. The invention alsoprovides pharmaceutically acceptable compositions comprising thecompounds of the invention and methods of using the compositions in thetreatment of various disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in allexcitable cells such as neurons and myocytes. They play key roles inexcitable tissue including brain, smooth muscles of the gastrointestinaltract, skeletal muscle, the peripheral nervous system, spinal cord andairway. As such they play key roles in a variety of disease states suchas epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy andsodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91)), pain(See, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels andpain” Proc Natl Acad Sci USA 96(14): 7635-9 and Waxman, S. G., T. R.Cummins, et al. (2000) “Voltage-gated sodium channels and the molecularpathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28),myotonia (See, Meola, G. and V. Sansone (2000) “Therapy in myotonicdisorders and in muscle channelopathies” Neurol Sci 21(5): S953-61 andMankodi, A. and C. A. Thornton (2002) “Myotonic syndromes” Curr OpinNeurol 15(5): 545-52), ataxia (See, Meisler, M. H., J. A. Kearney, etal. (2002) “Mutations of voltage-gated sodium channels in movementdisorders and epilepsy” Novartis Found Symp 241: 72-81), multiplesclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensoryneuron-specific sodium channel SNS is abnormally expressed in the brainsof mice with experimental allergic encephalomyelitis and humans withmultiple sclerosis” Proc Natl Acad Sci USA 97(21): 11598-602, andRenganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8sodium channels perturbs the firing patterns of cerebellar purkinjecells” Brain Res 959(2): 235-42), irritable bowel (See, Su, X., R. E.Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodiumcurrents in colon sensory neurons from rat dorsal root ganglia” Am JPhysiol 277(6 Pt 1): G1180-8, and Laird, J. M., V. Souslova, et al.(2002) “Deficits in visceral pain and referred hyperalgesia in Nav1.8(SNS/PN3)—null mice” J Neurosci 22(19): 8352-6), urinary incontinenceand visceral pain (See, Yoshimura, N., S. Seki, et al. (2001) “Theinvolvement of the tetrodotoxin-resistant sodium channel Na(v)1.8(PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6),as well as an array of psychiatry dysfunctions such as anxiety anddepression (See, Hurley, S. C. (2002) “Lamotrigine update and its use inmood disorders” Ann Pharmacother 36(5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9different subtypes (NaV1.1-NaV1.9). As shown in Table 1, these subtypesshow tissue specific localization and functional differences (See,Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu RevPhysiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5)are resistant to block by the well-known Na channel blocker TTX,demonstrating subtype specificity within this gene family. Mutationalanalysis has identified glutamate 387 as a critical residue for TTXbinding (See, Noda, M., H. Suzuki, et al. (1989) “A single pointmutation confers tetrodotoxin and saxitoxin insensitivity on the sodiumchannel II” FEBS Lett 259(1): 213-6).

TABLE 1 (Abbreviations: CNS = central nervous system, PNS = peripheralnervous sytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion): NaIsoform Tissue TTX IC50 Indications NaV1.1 CNS, PNS soma 10 nM Pain,Epilepsy, of neurons neurodegeneration NaV1.2 CNS, high in 10 nMNeurodegeneration axons Epilepsy NaV1.3 CNS, 15 nM Pain, Epilepsyembryonic, injured nerves NaV1.4 Skeletal 25 nM Myotonia muscle NaV1.5Heart 2 μM Arrythmia, long QT NaV1.6 CNS 6 nM Pain, movement widespread,disorders most abuntant NaV1.7 PNS, DRG, 25 nM Pain, terminalsNeuroendocrine neuroendocrine disorders NaV1.8 PNS, small >50 μM Painneurons in DRG & TG NaV1.9 PNS, small 1 μM Pain neurons in DRG & TG

In general, voltage-gated sodium channels (NaVs) are responsible forinitiating the rapid upstroke of action potentials in excitable tissuein nervous system, which transmit the electrical signals that composeand encode normal and aberrant pain sensations. Antagonists of NaVchannels can attenuate these pain signals and are useful for treating avariety of pain conditions, including but not limited to acute, chronic,inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX,lidocaine (See, Mao, J. and L. L. Chen (2000) “Systemic lidocaine forneuropathic pain relief” Pain 87(1): 7-17.) bupivacaine, phenyloin (See,Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See,Rozen, T. D. (2001) “Antiepileptic drugs in the management of clusterheadache and trigeminal neuralgia” Headache 41 Suppl 1: S25-32 andJensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8.), and carbamazepine(See, Backonja, M. M. (2002) “Use of anticonvulsants for treatment ofneuropathic pain” Neurology 59(5 Suppl 2): S14-7), have been shown to beuseful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops inthe presence of tissue injury or inflammation reflects, at least inpart, an increase in the excitability of high-threshold primary afferentneurons innervating the site of injury. Voltage sensitive sodiumchannels activation is critical for the generation and propagation ofneuronal action potentials. There is a growing body of evidenceindicating that modulation of NaV currents is an endogenous mechanismused to control neuronal excitability (See, Goldin, A. L. (2001)“Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94.).Several kinetically and pharmacologically distinct voltage-gated sodiumchannels are found in dorsal root ganglion (DRG) neurons. TheTTX-resistant current is insensitive to micromolar concentrations oftetrodotoxin, and displays slow activation and inactivation kinetics anda more depolarized activation threshold when compared to othervoltage-gated sodium channels. TTX-resistant sodium currents areprimarily restricted to a subpopulation of sensory neurons likely to beinvolved in nociception. Specifically, TTX-resistant sodium currents areexpressed almost exclusively in neurons that have a small cell-bodydiameter; and give rise to small-diameter slow-conducting axons and thatare responsive to capsaicin. A large body of experimental evidencedemonstrates that TTX-resistant sodium channels are expressed onC-fibers and are important in the transmission of nociceptiveinformation to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targetinga unique region of the TTX-resistant sodium channel (NaV1.8) resulted ina significant reduction in PGE₂-induced hyperalgesia (See, Khasar, S.G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium currentmediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20).More recently, a knockout mouse line was generated by Wood andcolleagues, which lacks functional NaV1.8. The mutation has an analgesiceffect in tests assessing the animal's response to the inflammatoryagent carrageenan (See, Akopian, A. N., V. Souslova, et al. (1999) “Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways” Nat Neurosci 2(6): 541-8.). In addition, deficit in bothmechano- and thermoreception were observed in these animals. Theanalgesia shown by the Nav1.8 knockout mutants is consistent withobservations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitroelectrophysiology experiments have all shown that the sodium channelNaV1.8 is selectively localized to the small sensory neurons of thedorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L.Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodiumchannel expressed by sensory neurons” Nature 379(6562): 257-62.). Theprimary role of these neurons is the detection and transmission ofnociceptive stimuli. Antisense and immunohistochemical evidence alsosupports a role for NaV1.8 in neuropathic pain (See, Lai, J., M. S.Gold, et al. (2002) “Inhibition of neuropathic pain by decreasedexpression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade ofneuropathic pain by antisense targeting of tetrodotoxin-resistant sodiumchannels in sensory neurons” Methods Enzymol 314: 201-13.). NaV1.8protein is upregulated along uninjured C-fibers adjacent to the nerveinjury. Antisense treatment prevents the redistribution of NaV1.8 alongthe nerve and reverses neuropathic pain. Taken together thegene-knockout and antisense data support a role for NaV1.8 in thedetection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states there is a remodeling of Na channeldistribution and subtype. In the injured nerve, expression of NaV1.8 andNaV1.9 are greatly reduced whereas expression of the TTX sensitivesubunit NaV1.3 is significantly upregulated in animal models ofneuropathic pain (See, Dib-Hajj, S. D., J. Fjell, et al. (1999)“Plasticity of sodium channel expression in DRG neurons in the chronicconstriction injury model of neuropathic pain.” Pain 83(3): 591-600 andKim, C. H., Youngsuk, O., et al. (2001) “The changes in expression ofthree subtypes of TTX sensitive sodium channels in sensory neurons afterspinal nerve ligation”. Mol. Brain Res. 95:153-61.) The timecourse ofthe increase in NaV1.3 parallels the appearance of allodynia in animalmodels subsequent to nerve injury. Up-regulation of Nav1.3 transcriptionis also observed in a rat model of diabetic neuropathy. (See, Craner, M.J., Klein, J. P. et al. (2002) “Changes of sodium channel expression inexperimental painful diabetic neuropathy.” Ann Neurol. 52(6): 786-92.The biophysics of the NaV1.3 channel is distinctive in that it showsvery fast repriming after inactivation following an action potential.This allows for sustained rates of high firing as is often seen in thepathophysiological activity accompanying neuropathic pain (See, Cummins,T. R., F. Aglieco, et al. (2001) “Nav1.3 sodium channels: rapidrepriming and slow closed-state inactivation display quantitativedifferences after expression in a mammalian cell line and in spinalsensory neurons” J Neurosci 21(16): 5952-61.). Human NaV1.3 channelproteins are expressed in the central and peripheral systems of man.(See, Chen, Y. H., Dale, T. J., et al. (2000) “Cloning, distribution andfunctional analysis of the type III sodium channel from human brain.”Eur. J. Neurosci. 12: 4281-89). Furthermore, in the periphery, NaV1.3channel proteins are detectable in injured but not uninjured humannerves indicating that NaV1.3 plays important physiological roles underpathophysiological conditions in humans as well. Given the strongcorrelation between increased NaV1.3 channel expression and neuronalhyperexcitability, inhibitors of NaV1.3 channels, and in particularselective ones, might therefore provide efficacious therapeutic agentswith less-severe side effects than nonselective Na_+ channel inhibitorsin the treatment of painful neuropathies. Similarly, NaV1.3overexpression may also be associated with increased epipleptic neuronalactivity as it is significantly upregulated in hippocampal pyramidalneurons of epileptic humans (See, Whitaker, W. R. J., Faull, M., et al.(2001) “Changes in the mRNAs encoding voltage-gated sodium channel typesII and III in human epileptic hippocampus.” Neurosci. 106(2): 275-285.);inhibitors with some selectivity against Nav1.3 could also beparticularly attractive anticonvulsants and neuroprotectants.

NaV1.9 is similar to NaV1.8 as it is selectively localized to smallsensory neurons of the dorsal root ganglion and trigeminal ganglion(See, Fang, X., L. Djouhri, et al. (2002). “The presence and role of thetetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptiveprimary afferent neurons.” J Neurosci 22(17): 7425-33.). It has a slowrate of inactivation and left-shifted voltage dependence for activation(See, Dib-Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodiumchannel with unique properties” Trends Neurosci 25(5): 253-9.). Thesetwo biophysical properties allow NaV1.9 to play a role in establishingthe resting membrane potential of nociceptive neurons. The restingmembrane potential of NaV1.9 expressing cells is in the −55 to −50 mVrange compared to −65 mV for most other peripheral and central neurons.This persistent depolarization is in large part due to the sustainedlow-level activation of NaV1.9 channels. This depolarization allows theneurons to more easily reach the threshold for firing action potentialsin response to nociceptive stimuli. Compounds that block the NaV1.9channel may play an important role in establishing the set point fordetection of painful stimuli.

In chronic pain states, nerve and nerve ending can become swollen andhypersensitive exhibiting high frequency action potential firing withmild or even no stimulation. These pathologic nerve swellings are termedneuromas and the primary Na channels expressed in them are NaV1.8 andNaV1.7 (See, Kretschmer, T., L. T. Happel, et al. (2002) “Accumulationof PN1 and PN3 sodium channels in painful human neuroma-evidence fromimmunocytochemistry” Acta Neurochir (Wien) 144(8): 803-10; discussion810.). NaV1.6 and NaV1.7 are also expressed in dorsal root ganglionneurons and contribute to the small TTX sensitive component seen inthese cells. NaV1.7 in particular may therefore be a potential paintarget in addition to it's role in neuroendocrine excitability (See,Klugbauer, N., L. Lacinova, et al. (1995) “Structure and functionalexpression of a new member of the tetrodotoxin-sensitivevoltage-activated sodium channel family from human neuroendocrine cells”Embo J 14(6): 1084-90).

NaV1.1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1mutations cause febrile seizures associated with afebrile partialseizures.” Neurology 57(4): 703-5.) and NaV1.2 (See, Sugawara, T., Y.Tsurubuchi, et al. (2001) “A missense mutation of the Na+ channel alphaII subunit gene Na(v)1.2 in a patient with febrile and afebrile seizurescauses channel dysfunction” Proc Natl Acad Sci USA 98(11): 6384-9) havebeen linked to epilepsy conditions including febrile seizures. There areover 9 genetic mutations in NaV1.1 associated with febrile seizures(See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations ofvoltage-gated sodium channels in movement disorders and epilepsy”Novartis Found Symp 241: 72-81)

Antagonists for NaV1.5 have been developed and used to treat cardiacarrhythmias. A gene defect in NaV1.5 that produces a largernoninactivating component to the current has been linked to long QT inman and the orally available local anesthetic mexilitine has been usedto treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997)“Pharmacological targeting of long QT mutant sodium channels.” J ClinInvest 99(7): 1714-20).

Several Na channel blockers are currently used or being tested in theclinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002)“Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1):85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3, and Guay, D. R. (2001) “Adjunctive agents in the management ofchronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold,M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatoryhyperalgesia.” Proc Natl Acad Sci USA 96(14): 7645-9), and neuropathicpain (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeuticconcentrations of local anaesthetics unveil the potential role of sodiumchannels in neuropathic pain” Novartis Found Symp 241: 189-201, andSandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotriginemonotherapy for control of neuralgia after nerve section” ActaAnaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See, An, R. H.,R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na+channels” Circ Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al.(1997) “Pharmacological targeting of long QT mutant sodium channels” JClin Invest 99(7): 1714-20); neuroprotection (See, Taylor, C. P. and L.S. Narasimhan (1997) “Sodium channels and therapy of central nervoussystem diseases” Adv Pharmacol 39: 47-98) and as anesthetics (See,Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations oflocal anaesthetics unveil the potential role of sodium channels inneuropathic pain.” Novartis Found Symp 241: 189-201).

Voltage-gated calcium channels are membrane-spanning, multi-subunitproteins that open in response to membrane depolarization, allowing Caentry from the extracellular milieu. Calcium channels were initiallyclassified based on the time and voltage-dependence of channel openingand on the sensitivity to pharmacological block. The categories werelow-voltage activated (primarily T-type) and high-voltage activated (L,N, P, Q or R-type). This classification scheme was replaced by anomenclature based upon the molecular subunit composition, as summarizedin Table I (Hockerman, G. H., et. al. (1997) Annu. Rev. Pharmacol.Toxicol. 37: 361-96; Striessnig, J. (1999) Cell. Physiol. Biochem. 9:242-69). There are four primary subunit types that make up calciumchannels—α₁, α₂δ, β and γ (See, e.g., De Waard et al. Structural andfunctional diversity of voltage-activated calcium channels. In IonChannels, (ed. T. Narahashi) 41-87, (Plenum Press, New York, 1996)). Theα₁ subunit is the primary determinant of the pharmacological propertiesand contains the channel pore and voltage sensor (Hockerman, G. H., et.al. (1997) Annu. Rev. Pharmacol. Toxicol. 37: 361-96; Striessnig, J.(1999) Cell. Physiol. Biochem. 9: 242-69). Ten isoforms of the α₁subunit are known, as indicated in Table I. The α₂δ subunit consists oftwo disulfide linked subunits, α₂, which is primarily extracellular anda transmembrane δ subunit. Four isoforms of α₂δ are known, α₂δ-1, α₂δ-2,α₂δ-3 and α₂δ-4. The β subunit is a non-glycosylated cytoplasmic proteinthat binds to the α₁ subunit. Four isoforms are known, termed β₁ to β₄.The γ subunit is a transmembrane protein that has been biochemicallyisolated as a component of Ca_(v)1 and Ca_(v)2 channels. At least 8isoforms are known (γ₁ to γ₈) (Kang, M. G. and K. P. Campbell (2003) J.Biol. Chem. 278: 21315-8). The nomenclature for voltage-gated calciumchannels is based upon the content of the α₁ subunit, as indicated inTable I. Each type of α₁ subunit can associate with a variety of β, α₂δor γ subunits, so that each Ca_(v) type corresponds to many differentcombinations of subunits.

Pharmacological Cav Nomenclature α₁ subunit name Ca_(v)1.1 α_(1S) L-typeCa_(v)1.2 α_(1C) L-type Ca_(v)1.3 α_(1D) L-type Ca_(v)1.4 α_(1F)Ca_(v)2.1 α_(1A) P- or Q-type Ca_(v)2.2 α_(1B) N-type Ca_(v)2.3 α_(1E)R-type Ca_(v)3.1 α_(1G) T-type Ca_(v)3.2 α_(1H) T-type Ca_(v)3.3 α_(1I)T-type

Ca_(v)2 currents are found almost exclusively in the central andperipheral nervous system and in neuroendocrine cells and constitute thepredominant forms of presynaptic voltage-gated calcium current.Presynaptic action potentials cause channel opening and neurotransmitterrelease is steeply dependent upon the subsequent calcium entry. Thus,Ca_(v)2 channels play a central role in mediating neurotransmitterrelease.

Ca_(v)2.1 and Ca_(v)2.2 contain high affinity binding sites for thepeptide toxins ω-conotoxin-MVIIC and ω-conotoxin-GVIA, respectively, andthese peptides have been used to determine the distribution and functionof each channel type. Ca_(V)2.2 is highly expressed at the presynapticnerve terminals of neurons from the dorsal root ganglion and neurons oflamina I and II of the dorsal horn (Westenbroek, R. E., et al. (1998) J.Neurosci. 18: 6319-30; Cizkova, D, et al. (2002) Exp. Brain Res. 147:456-63). Ca_(V)2.2 channels are also found in presynaptic terminalsbetween second and third order interneurons in the spinal cord. Bothsites of neurotransmission are very important in relaying paininformation to the brain.

Pain can be roughly divided into three different types: acute,inflammatory, and neuropathic. Acute pain serves an important protectivefunction in keeping the organism safe from stimuli that may producetissue damage. Severe thermal, mechanical, or chemical inputs have thepotential to cause severe damage to the organism if unheeded. Acute painserves to quickly remove the individual from the damaging environment.Acute pain by its very nature generally is short lasting and intense.Inflammatory pain, on the other hand, may last for much longer periodsof time and its intensity is more graded. Inflammation may occur formany reasons including tissue damage, autoimmune response, and pathogeninvasion. Inflammatory pain is mediated by a variety of agents that arereleased during inflammation, including substance P, histamines, acid,prostaglandin, bradykinin, CGRP, cytokines, ATP, and other agents(Julius, D. and A. I. Basbaum (2001) Nature 413 (6852): 203-10). Thethird class of pain is neuropathic and involves nerve damage arisingfrom nerve injury or viral infection and results in reorganization ofneuronal proteins and circuits yielding a pathologic “sensitized” statethat can produce chronic pain lasting for years. This type of painprovides no adaptive benefit and is particularly difficult to treat withexisting therapies.

Pain, particularly neuropathic and intractable pain is a large unmetmedical need. Millions of individuals suffer from severe pain that isnot well controlled by current therapeutics. The current drugs used totreat pain include NSAIDS, COX-2 inhibitors, opioids, tricyclicantidepressants, and anticonvulsants. Neuropathic pain has beenparticularly difficult to treat as it does not respond well to opioidsuntil high doses are reached. Gabapentin is currently the most widelyused therapeutic for the treatment of neuropathic pain, although itworks in only 60% of patients and has modest efficacy. The drug isgenerally safe, although sedation is an issue at higher doses.

Validation of Cav2.2 as a target for the treatment of neuropathic painis provided by studies with ziconotide (also known asω-conotoxin-MVIIA), a selective peptide blocker of this channel(Bowersox, S. S., et al. (1996) J. Pharmacol. Exp. Ther. 279: 1243-9;Jain, K. K. (2000) Exp. Opin. Invest. Drugs 9: 2403-10; Vanegas, H. andH. Schaible (2000) Pain 85: 9-18). In man, intrathecal infusion ofZiconotide is effective for the treatment of intractable pain, cancerpain, opioid resistant pain, and neuropathic pain. The toxin has an 85%success rate for the treatment of pain in humans with a greater potencythan morphine. An orally available antagonist of Ca_(V)2.2 should havesimilar efficacy without the need for intrathecal infusion. Ca_(V)2.1and Ca_(V)2.3 are also in neurons of nociceptive pathways andantagonists of these channels could be used to treat pain.

Antagonists of Ca_(V)2.1, Ca_(V)2.2 or Ca_(V)2.3 should also be usefulfor treating other pathologies of the central nervous system thatapparently involve excessive calcium entry. Cerebral ischaemia andstroke are associated with excessive calcium entry due to depolarizationof neurons. The Ca_(V)2.2 antagonist ziconotide is effective in reducinginfarct size in a focal ischemia model using laboratory animals,suggesting that Ca_(V)2.2 antagonists could be used for the treatment ofstroke. Likewise, reducing excessive calcium influx into neurons may beuseful for the treatment of epilepsy, traumatic brain injury,Alzheimer's disease, multi-infarct dementia and other classes ofdementia, amyotrophic lateral sclerosis, amnesia, or neuronal damagecaused by poison or other toxic substances.

Ca_(V)2.2 also mediates release of neurotransmitters from neurons of thesympathetic nervous system and antagonists could be used to treatcardiovascular diseases such as hypertension, cardiac arrhythmia, anginapectoris, myocardial infarction, and congestive heart failure.

However, as described above, the efficacy of currently used sodiumchannel blockers and calcium channel blockers for the disease statesdescribed above has been to a large extent limited by a number of sideeffects. These side effects include various CNS disturbances such asblurred vision, dizziness, nausea, and sedation as well more potentiallylife threatening cardiac arrhythmias and cardiac failure. Accordingly,there remains a need to develop additional Na channel antagonists, andCa channel antagonists preferably those with higher potency and fewerside effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium and/or calcium channels. Thesecompounds have the general formula I:T-L₁-A-L₂-Z  (I);or a pharmaceutically acceptable derivative thereof;

wherein:

L₁ is —(X₁)_(p)—(X₂)_(q)—R_(y)—;

-   -   wherein:    -   X₁ is O, S, or NR_(x)    -   p is 0 or 1;    -   q is 0 or 1;    -   R_(x) is H or R²;    -   X₂ is R²;

R_(y) is —C(O)—NR²—; or

L₂ and Ry are independently selected from OC(O), C(O)O, S(O), SO₂,N(R⁵)SO₂, N(R⁶)SO₂, SO₂N(R⁵), SO₂N(R⁶), C(O)N(R⁵), C(O)N(R⁶), NR⁵C(O),NR⁶C(O), C(NOR⁵)R⁶, C(NOR⁵)R⁶, C(NOR⁶)R⁵, C(NOR⁶)R⁶, N(R⁵), N(R⁶),NR⁵C(O)O, NR⁶C(O)O, OC(O)NR⁵, OC(O)NR⁶, NR⁵C(O)N(R⁵), NR⁵C(O)N(R⁶),NR⁶C(O)N(R⁵), NR⁶C(O)N(R⁶), NR⁵SO₂N(R⁵), NR⁵SO₂N(R⁶), NR⁶SO₂N(R⁵),NR⁶SO₂N(R⁶), N(OR⁵), or N(OR⁶);

Z is hydrogen, cycloaliphatic, heterocyclic, aryl, or heteroaryl ring;

T is aliphatic, cycloaliphatic, aryl, heteroaryl, or heterocyclic ring;

A is aryl or heteroaryl ring;

wherein each of T, A, and Z optionally comprises up to 4 suitablesubstituents independently selected from R¹, R², R³, R⁴, or R⁵;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), R⁶ or (CH₂)_(n)—Y;

n is 0, 1 or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶; or

two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxyor 1,2-ethylenedioxy;

R² is aliphatic, wherein each R² is optionally substituted with up to 2substituents independently selected from R¹, R⁴, or R⁵;

R³ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ringoptionally substituted with up to 3 substituents, independently selectedfrom R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂,NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶,N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶),P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂,P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ringoptionally substituted with up to 3 R¹ substituents;

R⁶ is H or aliphatic, wherein R⁶ is optionally substituted with a R⁷substituent;

R⁷ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring and eachR⁷ is optionally substituted with up to 2 substituents independentlychosen from H, aliphatic, or (CH₂)_(n)-Z;

Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo),—OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S-aliphatic, S(O)-aliphatic,SO₂-aliphatic, NH₂, NH-aliphatic, N(aliphatic)₂, N(aliphatic)R⁸, COOH,C(O)O(-aliphatic), or O-aliphatic; and

R⁸ is an amino protecting group.

These compounds and pharmaceutically acceptable compositions thereof areuseful for treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, and incontinence.

DESCRIPTION OF THE FIGURES

FIG. 1 (FIG. 1-1 to FIG. 1-248) depicts the structures of the compoundsof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

According to one embodiment, the present invention provides compounds offormula (I) useful in inhibiting a sodium and/or calcium channel:T-L₁-A-L₂-Z  (I);or a pharmaceutically acceptable salt thereof;

wherein:

L₁ is —(X₁)_(p)—(X₂)_(q)—R_(y)—;

-   -   wherein:    -   X₁ is O, S, or NR_(x)    -   p is 0 or 1;    -   q is 0 or 1;    -   R_(x) is H or R²;    -   X₂ is R²;

R_(y) is —C(O)—NR²—; or

L₂ and Ry are independently selected from OC(O), C(O)O, S(O), SO₂,N(R⁵)SO₂, N(R⁶)SO₂, SO₂N(R⁵), SO₂N(R⁶), C(O)N(R⁵), C(O)N(R⁶), NR⁵C(O),NR⁶C(O), C(NOR⁵)R⁶, C(NOR⁵)R⁶, C(NOR⁶)R⁵, C(NOR⁶)R⁶, N(R⁵), N(R⁶),NR⁵C(O)O, NR⁶C(O)O, OC(O)NR⁵, OC(O)NR⁶, NR⁵C(O)N(R⁵), NR⁵C(O)N(R⁶),NR⁶C(O)N(R⁵), NR⁶C(O)N(R⁶), NR⁵SO₂N(R⁵), NR⁵SO₂N(R⁶), NR⁶SO₂N(R⁵),NR⁶SO₂N(R⁶), N(OR⁵), or N(OR⁶);

Z is hydrogen, cycloaliphatic, heterocyclic, aryl, or heteroaryl ring;

T is aliphatic, cycloaliphatic, aryl, heteroaryl, or heterocyclic ring;

A is aryl or heteroaryl ring;

wherein each of T, A, and Z is optionally substituted with up to 4suitable substituents independently selected from R¹, R², R³, R⁴, or R⁵;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), R⁶ or (CH₂)_(n)—Y;

n is 0, 1 or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶; or

two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxyor 1,2-ethylenedioxy;

R² is aliphatic, wherein each R² is optionally substituted with up to 2substituents independently selected from R¹, R⁴, or R⁵;

R³ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring isoptionally substituted with up to 3 substituents, independently selectedfrom R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵; C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂,NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶,N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶),P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂,P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring isoptionally substituted with up to 3 R¹ substituents;

R⁶ is H or aliphatic, wherein R⁶ is optionally substituted with a R⁷substituent;

R⁷ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring and eachR⁷ is optionally substituted with up to 2 substituents independentlychosen from H, aliphatic, or (CH₂)_(n)-Z′;

Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo),—OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S-aliphatic, S(O)-aliphatic,SO₂-aliphatic, NH₂, NH-aliphatic, N(aliphatic)₂, N(aliphatic)R⁸, COOH,C(O)O(-aliphatic), or O-aliphatic; and

R⁸ is an amino protecting group.

According to one embodiment, the present invention provides compounds offormula I′:

or a pharmaceutically acceptable salt thereof,wherein:

X₁ is O, S, or NR_(x);

-   -   p is 0 or 1;    -   q is 0 or 1;    -   R_(x) is H or R²;    -   X₂ is a bond R²;    -   L₂ is selected from OC(O), C(O)O, S(O), SO₂, N(R⁵)SO₂, N(R⁶)SO₂,        SO₂N(R⁵), SO₂N(R⁶), C(O)N(R⁵), C(O)N(R⁶), NR⁵C(O), NR⁶C(O),        C(NOR⁵)R⁶, C(NOR⁵)R⁶, C(NOR⁶)R⁵, C(NOR⁶)R⁶, N(R⁵), N(R⁶),        NR⁵C(O)O, NR⁶C(O)O, OC(O)NR⁵, OC(O)NR⁶, NR⁵C(O)N(R⁵),        NR⁵C(O)N(R⁶), NR⁶C(O)N(R⁵), NR⁶C(O)N(R⁶), NR⁵SO₂N(R⁵),        NR⁵SO₂N(R⁶), NR⁶SO₂N(R⁵), NR⁶SO₂N(R⁶), N(OR⁵), or N(OR⁶);

Z is cycloaliphatic, heterocyclic, aryl, or heteroaryl ring;

T is aliphatic, cycloaliphatic, aryl, heteroaryl, or heterocyclic ring;

A is aryl or heteroaryl ring;

wherein each of T, A, and Z is optionally substituted with up to 4suitable substituents independently selected from R¹, R², R³, R⁴, or R⁵;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), R⁶ or (CH₂)_(n)—Y;

n is 0, 1 or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶; or

two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxyor 1,2-ethylenedioxy;

R² is aliphatic, wherein each R² is optionally substituted with up to 2substituents independently selected from R¹, R⁴, or R⁵;

R³ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring,optionally substituted with up to 3 substituents, independently selectedfrom R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂,NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶,N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶),P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂,P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring isoptionally substituted with up to 3 R¹ substituents;

R⁶ is H or aliphatic, wherein R⁶ is optionally substituted with a R⁷substituent;

R⁷ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring and eachR⁷ is optionally substituted with up to 2 substituents independentlychosen from H, aliphatic, or (CH₂)_(n)-Z′;

Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo),—OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S-aliphatic, S(O)-aliphatic,SO₂-aliphatic, NH₂, NH-aliphatic, N(aliphatic)₂, N(aliphatic)R⁸, COOH,C(O)O(-aliphatic), or O-aliphatic; and

R⁸ is an amino protecting group.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable (i.e.,having the requisite valency available for a given substituent) positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups. The term “cycloaliphatic” means a monocyclichydrocarbon, bicyclic, or tricyclic hydrocarbon that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic and has a single point of attachment to the rest of themolecule. In some embodiments, “cycloaliphatic” refers to a monocyclicC₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic, that has a single point of attachment to the rest ofthe molecule wherein any individual ring in said bicyclic ring systemhas 3-7 members.

Unless otherwise specified, the term “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, or “heterocyclic” as used herein meansnon-aromatic, monocyclic, bicyclic, or tricyclic ring systems in whichone or more ring atoms in one or more ring members is an independentlyselected heteroatom. Heterocyclic ring can be saturated or can containone or more unsaturated bonds. In some embodiments, the “heterocycle”,“heterocyclyl”, or “heterocyclic” group has three to fourteen ringmembers in which one or more ring members is a heteroatom independentlyselected from oxygen, sulfur, nitrogen, or phosphorus, and each ring inthe ring system contains 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus,or silicon; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring carbon atoms, wherein at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 7 ring carbon atoms.The term “aryl” may be used interchangeably with the term “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

According to a preferred embodiment, p is 0, and q is 0.

According to another preferred embodiment, p is 0, and q is 1. Or, p is1, and q is 0.

According to yet another preferred embodiment, p is 1 and q is 1.

According to a preferred embodiment, X₁ is O or NR_(x). More preferably,X₁ is O. According to another embodiment, X₁ is NR_(x); preferably R_(x)is H. Or, X₁ is S.

According to a preferred embodiment, X₂ is a straight or branched(C1-C6)alkyl or (C2-C6)alkenyl or alkynyl, optionally substituted withup to two substituents independently selected from R₁ and R₅. Morepreferably, X₂ is a straight or branched (C1-C6)alkyl optionallysubstituted with up to two substituents independently selected from R₁and R₅. Preferred X₂ include C1-4 alkyl, such as, —CH₂—, CH₂CH₂, or—CH₂CH₂CH₂—.

According to a preferred embodiment of formula (I), R_(y) is —C(O)—NH—or —C(O)—NR²—. More preferably, R² is straight or branched (C1-C6)alkylor (C2-C6)alkenyl or alkynyl, optionally substituted with up to twosubstituents independently selected from R₁ and R₅. More preferably,R_(y) is —C(O)—NH—.

In one embodiment, L₂ is selected from N(R⁵)SO₂, N(R⁶)SO₂, SO₂N(R⁵),SO₂N(R⁶), C(O)N(R⁵), C(O)N(R⁶), NR⁵C(O), NR⁶C(O), NR⁵C(O)O, NR⁶C(O)O,OC(O)NR⁵, OC(O)NR⁶, NR⁵C(O)N(R⁵), NR⁵C(O)N(R⁶), NR⁶C(O)N(R⁵), orNR⁶C(O)N(R⁶).

In another embodiment, L₂ is selected from N(R⁶)SO₂, SO₂N(R⁶),C(O)N(R⁶), NR⁶C(O), NR⁶C(O)O, OC(O)NR⁶, or NR⁶C(O)N(R⁶). Preferably, R⁶is hydrogen.

In another embodiment, L₂ is selected from NHSO₂, SO₂NH, C(O)NH, orNHC(O).

According to another preferred embodiment, Z is cycloaliphatic,heterocyclic, aryl, or heteroaryl ring.

According to a preferred embodiment of formula (I), Z is aryl orheteroaryl. More preferably, Z is phenyl or napthyl. According to a morepreferred embodiment, Z is heteroaryl. More preferably, Z is selectedfrom thiazole, isothiazole, thiadiazole, thiaphene, furan, oxazole,isooxazole, oxadiazole, triazole, imidazole, pyrazole, pyridine,pyrimidine, pyrazine, pyridazine, triazine, or pyrrolyl.

According to a preferred embodiment of formula (I), A is aryl. Morepreferably, A is phenyl or naphthyl. Most preferably, A is phenyl.

According to another preferred embodiment of formula (I), A isheteroaryl. More preferably, A is a monocyclic aromatic ring containing1 to 3 heteroatoms. More preferably, A is pyridyl, pyrazyl, triazinyl,furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, imidazolyl, triazolyl, thiadiazolyl, or pyrimidinyl.According to another preferred embodiment of formula (I), A is abicyclic ring system with at least one aromatic ring, wherein said ringsystem contains 1-5 heteroatoms. More preferably, A is quinolinyl,isoquinolinyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl,benzofuranyl, benzothiophenyl, indolizinyl, indolyl, isoindolyl,indolinyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl,cinnolinyl, phthalazine, quinazolinyl, quinaoxalinyl, naphthylirinyl, orpteridinyl. According to another preferred embodiment, A is a tricyclicring system with at least one aromatic ring, wherein said ring systemcontains 1-5 heteroatoms. More preferably, A is dibenzofuranyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl.

According to a preferred embodiment of formula (I), T is aliphatic orcycloaliphatic. According to a preferred embodiment T is aliphatic; morepreferably, (C1-C6) straight or branched alkyl; yet more preferably,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. Accordingto another preferred embodiment, T is cycloaliphatic; more preferably,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, oradamantyl. Yet more preferably, T is cyclopropyl, cyclohenxyl,norbornyl, or adamantyl.

According to another preferred embodiment, T is an aryl ring; morepreferably, phenyl, napthyl, or anthracenyl. Yet more preferably, T isphenyl or napthyl. According to another preferred embodiment, T is aheteroaryl ring; more preferably, thiophenyl, benzothiophenyl, pyridyl,furanyl, benzofuranyl, oxazolyl, quinolinyl, thiophenyl,benzothiophenyl, pyridiyl, furanyl, benzofuranyl, oxazolyl, quinolinyl,pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl,benzimidazolyl, benzthiazolyl, purinyl, isoquinolinyl, cinnolinylphthalazinyl, quinazolinyl, quinoxalinyl, napthyridinyl, pteridinyl,acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, carbazolyl.

In one embodiment, T is selected from:

wherein T is optionally substituted with up to three substituentsindependently selected from phenyl optionally substituted with R¹, halo,cyano, trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

According to another preferred embodiment, T is a heterocyclic ring;preferably, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl,dithianyl, thiomorpholinyl, piperazinyl, quinuclidinyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, dithianyl,thiomorpholinyl, piperazinyl, quinuclidinyl, dioxoianyl, imidazolidinyl,pyrazolidinyl, dioxanyl, piperazinyl, or trithianyl.

According to another preferred embodiment of formula (I), R¹ is oxo.According to another preferred embodiment, R¹ is R⁶ or (CH₂)_(n)—Y; morepreferably, R¹ is Y (i.e., n is 0).

According to another preferred embodiment of formula (I), R² is astraight or branched (C1-C6) alkyl or (C2-C6)alkenyl or alkynyl,optionally substituted with up to two R¹ substitutions.

According to one embodiment, R¹ is (CH₂)_(n)—Y. Or, R¹ is Y.

Preferred Y includes halo, CN, NO₂, CF₃, OCF₃, OH, SH, S(C1-4aliphatic), S(O)(C1-4 aliphatic), SO₂(C1-4 aliphatic), NH₂, NH(C1-4aliphatic), N(C1-4 aliphatic)₂, NR(C1-4 aliphatic)R⁸, COOH, COO(C1-4aliphatic) or O(C1-4 aliphatic). Or two R¹ on adjacent ring atoms, takentogether, form 1,2-methylenedioxy or 1,2-ethylenedioxy;

According to another embodiment, R¹ is selected from halo, cyano,trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, orC(O)C₁₋₄ alkyl.

According to another preferred embodiment of formula (I):

Z is thiazol-2-yl;

A is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, ortetrazinyl;

L₁ is —(X₁)_(p)—(X₂)_(q)—R_(y)—;

-   -   wherein:    -   X₁ is O, S, or NR_(x)    -   p is 0 or 1;    -   q is 0 or 1;    -   R_(x) is H or R²;    -   X₂ is R²;    -   R_(y) is —C(O)—NH—; and

L₂ is SO₂N(R⁵) or SO₂N(R⁶).

According to one embodiment, the present invention provides a compoundof formula I-A:

wherein:

-   -   X₁ is O, S, or NR^(x)    -   p is 0 or 1;    -   R^(x) is H or R²;    -   R^(N) is hydrogen or C1-4 aliphatic optionally substituted with        up to two substituents selected from R¹, R⁴, or R⁵;    -   X₂ is C1-3 aliphatic, optionally substituted with up to 2        substituents independently selected from R¹, R⁴, or R⁵;

Z is a 5-7 membered unsaturated or aromatic ring having 1-4 heteroatomsselected from O, S, SO, SO₂, N, or NH;

T is a 8-14 membered aromatic or non-aromatic bicyclic or tricyclicring, having 0-5 heteroatoms selected from O, S, N, NH, S(O) or SO₂;

wherein each of Z and T is optionally substituted with up to 4substituents independently selected from R¹, R², R³, R⁴, or R⁵;

wherein the phenylene ring attached to the sulfonyl is optionallysubstituted with up to 3 substituents selected from R¹ and R²;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), R⁶ or (CH₂)_(n)—Y;

n is 0, 1 or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶; or

two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxyor 1,2-ethylenedioxy;

R² is aliphatic, wherein each R² is optionally substituted with up to 2substituents independently selected from R¹, R⁴, or R⁵;

R³ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring isoptionally substituted with up to 3 substituents, independently selectedfrom R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂,NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶,N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶),P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂,P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ringoptionally is optionally substituted with up to 3 R¹ substituents;

R⁶ is H or aliphatic, wherein R⁶ is optionally substituted with a R⁷substituent;

R⁷ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring and eachR⁷ is optionally substituted with up to 2 substituents independentlychosen from H, aliphatic, or (CH₂)_(n)-Z′;

Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo),—OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S-aliphatic, S(O)-aliphatic,SO₂-aliphatic, NH₂, NH-aliphatic, N(aliphatic)₂, N(aliphatic)R⁸, COOH,C(O)O(-aliphatic), or O-aliphatic; and

R⁸ is an amino protecting group.

In certain embodiments, compounds of formula I or formula I-A excludethe following:

a) when both R^(N) are hydrogen, and T is isoindol-1,3-dione-2-yloptionally substituted with up to 4 halo atoms, then Z is not pyridyl,thiazol-2-yl, 4-(4-methoxyphenyl)thiazol-2-yl,2-ethyl-1,3,4-thiadiazol-5-yl, optionally substituted pyrimidin-2-yl,5-methyl-isoxazolyl, 3,4-dimethyl-isoxazoly, or 2-methyl-isoxazolyl;

b) when both R^(N) are hydrogen, and T is

optionally substituted with up to 4 halo atoms, wherein R^(mm) is phenyloptionally substituted with C₁₋₄ alkyl or hydrogen, then Z is notoptionally substituted pyrimidin-2-yl, 2-pyridyl, or thiazol-2-yl;

c) when both R^(N) are hydrogen, X₂ is —CH₂—, p is 1, X₁ is S, and T is

then Z is not 3,4-dimethylisoxazolyl, pyrimidin-2-yl, thiazol-2-yl, or4,6-dimethyl-pyrimidin-2-yl;

c) when both R^(N) are hydrogen, X₂ is —CH₂— and X₁ is S, or X₂ is CH═CHand X₁ is absent, and T is optionally substituted

wherein Y′ is O, S, or NH, then Z is not pyrimidinyl optionallysubstituted with up to 2 methyl or methoxy groups, 2-pyridyl,thiazol-2-yl, 2-methoxy-pyrazin-3-yl, 3-chloro-pyridazin-6-yl,3,4-dimethyl-isoxazolyl, or 2-ethyl-1,3,4-thiadiazol-5-yl;

d) when both R^(N) are hydrogen, X₂ is —CH₂—CH₂—, X₁ is absent, and T is

then Z is not thiazol-2-yl, 2,6-dimethyl-pyrimidin-4-yl, or3,4-dimethyl-isoxazol-5-yl;

e) when both R^(N) are hydrogen, X₂ is —CH₂—, X₁ is O or S, and T is

wherein Y² is O or CH₂, then Z is not thiazol-2-yl, or4,6-dimethyl-pyrimidin-2-yl, or pyrimidin-2-yl;

f) when both R^(N) are hydrogen, X₂ is —CH₂—, X₁ is O, T is

wherein R^(nn) is hydrogen or halo, then Z is not thiazol-2-yl,4-methyl-pyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, pyrimidin-2-yl, or5-methyl-isoxazol-3-yl;

g) when both R^(N) are hydrogen, X₂ is —CH₂—, X₁ is absent, T is1,4-dihydro-quinoxalin-2,3-dione-4-yl, then Z is not5-methylisoxazol-3-yl, thiazol-2-yl, 4,6-dimethyl-pyrimidin-2-yl,pyrimidin-2-yl, or 2-pyridyl;

h) when both R^(N) are hydrogen, X₂ is —CH₂—, X₁ is absent, and T is2,3-dihydro-phthalazin-1,4-dione-2-yl, then Z is not pyridyl,thiazol-2-yl, or optionally substituted pyrimidin-2-yl;

i) when both R^(N) are hydrogen, X₂ is —CH₂—, X₁ is absent, and T isadamantyl or haloadamantyl, then Z is not 3,4-dimethylisoxazol-5-yl,thiazol-2-yl, or 4-methyl-pyrimidin-2-yl;

j) the following compounds in Table A, wherein R^(N) is hydrogen, areexcluded:

TABLE A ring Z X₂ X₁ ring T pyrimidin-2-yl CH₂ NH 1-naphthyl4,6-dimethyl-pyrimidin-2-yl CH₂ NH 1-naphthyl 5-methyl-isoxazol-3-yl CH₂— 1-naphthyl thiazol-2-yl CH₂ O 1-naphthyl, 2-napthyl,1,7-dibromo-naphth-2-yl 4,6-dimethyl-pyrimidin-2-yl CH₂ O 1-naphthyl,2-napthyl, or 1,7-dibromo-naphth- 2-yl 2-methoxy-pyrazin-3-yl CH₂ O2-napthyl 5-ethyl-1,3,4-thiadiazol-2-yl CH₂ — 1-napthyl thiazol-2-yl CH₂— 1-naphtyl 5-ethyl-1,3,4-thiadiazol-2-yl CH₂ O 2-naphthyl2,6-dimethoxy-pyrimidin-4-yl CH₂ O 1-bromo-2-naphthyl2,6-dimethyl-pyrimidin-4-yl CH₂ O 2-naphthyl or 1-bromo- 2-naphthyl2,6-dimethoxy-pyrimidin-4-yl CH₂ O 1-naphthyl or 2- naphthyl2,4-dimethoxy-pyrimidin-6-yl CH═CH — 1-naphthyl4,6-dimethyl-pyrimidin-2-yl CH═CH — 1-naphthyl 5-methyl-isoxazol-3-ylCH₂ O 1-naphthyl or 2- naphthyl 5-methyl-isoxazol-3-yl CH₂ O1-bromo-2-naphthyl or 1,7-dibromo-naphth-2-yl 4,5-dimethyl-isoxazol-3-ylCH₂ S 4-bromo-7-chloro- naphth-1-yl thiazol-2-yl CH₂ S 4-bromo-7-chloro-naphth-1-yl 4,6-dimethyl-pyrimidin-2-yl CH₂ O or S 2-naphtyl3,4-dimethyl-isoxazol-2-yl CH₂ O or S 2-naphthyl4,6-dimethyl-pyrimidin-2-yl CH₂ S quinolin-8-yl2,6-dimethyl-pyrimidin-2-yl CH₂ — 1-naphthyl pyrimidin-2-yl CH₂ —1-naphthyl 6-methoxy-pyrimidin-4-yl CH₂ — 1-naphthyl 2-pyridyl CH₂ —1-naphthyl 4-methyl-pyrimidin-2-yl CH₂ O 2-naphthyl pyrimidin-2-yl CH₂ O2-naphthyl 2,4-dimethoxy-pyrimidin-2-yl CH₂ O 1,7-dibromo-naphth-2-yl2,4-dimethoxy-pyrimidin-2-yl CH₂ — 1-naphthyl or2,4-dimethyl-pyrimidin-2- yl thiazol-2-yl or 2,4-dimethyl-pyrimidin-4-ylCH₂ S isoquinolin-1-yl or 4- methyl-quinazolin-2-yl;

k) the following compounds in Table B, wherein R^(N) is hydrogen, areexcluded:

TABLE B Ring Z X₂, X₁, and T, together

wherein the asterisk in each structure fragment denotes the carbon atomattached to the remainder of the molecule; e.g., the fragment -* denotesan ethyl group, wherein the second atom of that ethyl group is attachedto the remainder of the molecule.

In one embodiment, T is attached to X₁ or to X₂ (when X₁ is absent)through a carbon ring atom in T.

In one embodiment, Z is an optionally substituted ring selected from:

In certain embodiments of the compounds of the present invention, Z isselected from:

wherein Z has up to two substituents selected from R¹, R², or R⁵.

In other embodiments, Z is selected from:

Or, Z is formula i-a.

In other embodiments, Z is selected from:

In certain embodiments of the present invention, Z is selected from:

Or, Z is selected from:

Or, Z is selected from:

In certain embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In other embodiments, Z is selected from:

In other embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In other embodiments, Z is selected from:

In certain embodiments, R^(N) is hydrogen. Or, R^(N) is unsubstitutedC1-4 alkyl.

In one embodiment, X² is selected from —CH₂—, —CH₂—CH₂—, —(CH₂)₃—,—C(Me)₂—, —CH(Me)—, —C(Me)═CH—, —CH═CH—, —CH(Ph)—, —CH₂—CH(Me)—,—CH(Et)-, —CH(i-Pr)—, or cyclopropylene.

In another embodiment, p is 1 and X₁ is O.

In another embodiment, p is 1, and X₁ is S.

In another embodiment, p is 1, and X₁ is NR^(N). Preferably, R^(N) ishydrogen.

In certain embodiments of the present invention, T is naphthyl,tetralinyl, decalinyl, or 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl,optionally substituted with up to 3 substituents independently selectedfrom halo, cyano, trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, orC(O)C₁₋₄ alkyl.

Or, T is optionally substituted napthyl.

In another embodiment, T is selected from:

wherein T is optionally substituted with up to three substituentsindependently selected from halo, cyano, trifluoromethyl, OH, C₁₋₄alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, trifluoromethoxy, C(O)NH₂, NH₂,NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

In another embodiment, T is a 5-membered ring having up to 4 heteroatomsselected from O, S, N, or NH, optionally fused to a phenyl ring, whereinsaid phenyl ring is unsubstituted or substituted with up to 4substituents selected from R¹ or R². Preferred 5-membered rings in suchembodiments of T include formula i through xxiii defined above for ringZ that are capable of being fused to a phenyl ring.

In other embodiments, T is selected from:

wherein T is optionally substituted with up to three substituentsindependently selected from halo, cyano, trifluoromethyl, OH, C₁₋₄alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, trifluoromethoxy, C(O)NH₂, NH₂,NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

In one embodiment, the phenylene ring attached to the sulfonyl group isoptionally substituted with up two substituents selected from halo,cyano, trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, or C(O)β1-4 alkyl.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z is thiazol-2-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is absent or is C1-4 alkylene optionally substituted with        phenyl;    -   d. X₁ is absent or is O or S;    -   e. T is selected from quinolin-4-yl, benzofuran-2-yl,        benzothiophen-3-yl, phenyl, tetralin-2-yl, tetralin-6-yl,        phenyl, indol-2-yl, chroman-3-yl, quinolin-3-yl,        benzo[1,3]oxathiol-2-one-6-yl, benzothiophen-2-yl,        1,2,3,4-tetrazol-5-yl, furan-5-yl, quinolin-5-yl,        benzothiazol-5-yl, or 5,6,7,8-tetrahydroquinolin-2-yl,        optionally substituted with up to three substituents selected        from trifluoromethyl, halo, cyano, C1-4 alkoxy,        piperidinylsulfonyl, C1-4 alkyl, phenyl optionally substituted        with up to three halo, cyano, C1-4 alkyl, or C1-4 alkoxy.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z is thiazol-2-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is absent or is C1-4 alkylene optionally substituted with        phenyl;    -   d. X₁ is absent or is O or S;    -   e. T is selected from 8-trifluoromethyl-quinolin-4-yl,        benzofuran-2-yl, benzothiophen-3-yl, 3-fluoro-4-chloro-phenyl,        8-methoxy-tetralin-2-yl, tetralin-6-yl,        4-piperidinylsulfonylphenyl, 2,4-dichlorophenyl,        5-fluoroindol-2-yl, 4,6-dichloroindol-2-yl, chroman-3-yl,        2-methyl-6-fluoro-quinolin-4-yl, 2,7-dimethyl-quinolin-3-yl,        4-trifluoromethylphenyl, 2-fluoro-4-chloro-phenyl,        benzo[1,3]oxathiol-2-one-6-yl, 5-chloro-benzothiophen-2-yl,        1-phenyl-1,2,3,4-tetrazol-5-yl,        2-(3′,5′-dichlorophenyloxy)-furan-5-yl,        5-fluoro-benzothiophen-2-yl, quinolin-5-yl,        2-methyl-quinolin-4-yl, 2-methyl-benzothiazol-5-yl, or        4-cyano-5,6,7,8-tetrahydroquinolin-2-yl.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z is thiazol-2-yl or 1,2,4-thiadiazol-5-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is absent or C1-4 alkylene;    -   d. X₁ is absent or O;    -   e. T is selected from phenyl, benzo[1,3]oxathiol-2-one-5-yl,        benzothiophen-2-yl, benzofuran-2-yl, quinolin-4-yl,        indolin-2-yl, 1,2,3,4-tetrazol-5-yl,        5,6,7,8-tetrahydroquinolin-2-yl, indol-2-yl, norbornyl,        furan-2-yl, 2-naphthyl, benzothiophen-3-yl, phenyl,        quinolin-7-yl, tetralin-6-yl, benzothiophen-3-yl, tetralin-2-yl,        chroman-3-yl, benzo[1,2,5]oxadiazol-5-yl, quinolin-5-yl,        benzothiazol-5-yl, indol-5-yl, quinolin-3-yl,        1,2,3,4-tetrahydroisoquinolin-3-yl, quinolin-2-yl,        benzo-[1,3]-dioxolan-5-yl, or benzo-[1,3]dixolan-4-yl, wherein T        is optionally substituted with up to three substituents        independently selected from trifluoromethyl, trifluoromethoxy,        halo, cyano, C1-4 alkoxy, C1-4 alkyl, acyl, N(C1-4alkyl)2,        phenyloxy or phenyl optionally substituted with up to three        halo, cyano, C1-4 alkyl, or C1-4 alkoxy.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z is thiazol-2-yl or 1,2,4-thiadiazol-5-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is absent or C1-4 alkylene;    -   d. X₁ is absent or O;    -   e. T is selected from 4-trifluoromethylphenyl,        3-fluoro-4-chlorophenyl, 2-chloro-4-cyanophenyl,        2,3-dichlorophenyl, benzo[1,3]oxathiol-2-one-5-yl,        5-fluorobenzothiophen-2-yl, 3,4-dichlorophenyl, benzofuran-2-yl,        8-trifluoromethyl-quinolin-4-yl, 2-chloro-4-cyanophenyl,        1-acyl-indolin-2-yl, 1-phenyl-1,2,3,4-tetrazol-5-yl,        2-fluoro-3-chlorophenyl, 2-methyl-4-fluorophenyl,        2,3-difluorophenyl, 3-cyano-5,6,7,8-tetrahydroquinolin-2-yl,        2-chlorophenyl, 5-fluoro-indol-2-yl, 2,4-dichlorophenyl,        3,5-dichlorophenyl, 3-chlorophenyl, 5-bromo-indol-2-yl,        4-chlorophenyl, 1-norbornyl, 2-methoxy-4-chlorophenyl,        5-(3′,5′-dichlorophenyloxy)-furan-2-yl, 2-naphthyl,        benzothiophen-3-yl, 2-fluoro-3-trifluoromethylphenyl,        2-methyl-4-chlorophenyl, quinolin-7-yl, 2-fluoro-6-chlorophenyl,        2-methyl-6-fluoro-quinolin-4-yl, 5-methoxy-benzofuran-2-yl,        phenyl, 3,4-difluorophenyl, 4,6-dichloroindol-2-yl,        2-trifluoromethoxyphenyl, 4-fluorophenyl,        5-chlorobenzothiophen-2-yl, 2-methyl-quinolin-4-yl,        tetralin-6-yl, 2,6-dimethylphenyl, benzothiophen-3-yl,        8-methoxy-tetralin-2-yl, 2-methoxy-4-methylphenyl, chroman-3-yl,        3,4-dicyanophenyl, 2,6-dimethyl-4-cyanophenyl,        benzo[1,2,5]oxadiazol-5-yl, 3-diethylaminophenyl, quinolin-5-yl,        2-methyl-benzothiazol-5-yl, 8-fluoro-quinolin-4-yl,        3-trifluoromethoxyphenyl, 2-chloro-3-trifluoromethylphenyl,        2-aminocarbonyl-phenyl, 2,3-dimethyl-indol-5-yl, 3-cyanophenyl,        7-dimethyl-quinolin-3-yl,        1-acyl-1,2,3,4-tetrahydroisoquinolin-3-yl,        4-methyl-quinolin-2-yl, benzo-[1,3]-dioxolan-5-yl, or        2,2-difluoro-benzo-[1,3]dixolan-4-yl.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z is thiazol-2-yl, oxazol-2-yl, 1,3,4-thiadiazol-2-yl,        1,2,4-thiadiazol-5-yl, wherein Z is optionally substituted with        CF₃, C1-4 alkyl, or C1-4 alkyl substituted with phenyl having        0-3 halo substituents. Preferably, Z is thiazol-2-yl,        5-benzyl-thiazol-2-yl, 5-(4′-chlorobenzyl)-oxazol-2-yl,        5-trifluoromethyl-1,3,4-thiadiazol-2-yl,        5-(2′-chlorobenzyl)-1,3,4-thiadiazol-2-yl,        5-cyclopropyl-1,3,4-thiadiazol-2-yl,        3-ethyl-1,2,4-thiadiazol-2-yl, or        5-(2′,3′-dichlorobenzyl)-thiazol-2-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is C1-3 alkylene;    -   d. X₁ is O or is absent; and    -   e. T is phenyl or 3-methyl-1,2,3,4-tetrahydro-isoquinolin-2-yl,        wherein T has up to 2 substituents selected from halo, cyano,        trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,        trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,        NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl. Preferably, T is        2,4-dichlorophenyl or        3-methyl-1,2,3,4-tetrahydro-isoquinolin-2-yl.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z is selected from thiazol-2-yl, 1,2,4-thiadiazol-5-yl,        2-pyrazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-4-yl, or        1,2,3,4-thiatriazol-5-yl, optionally substituted with up to two        substituents selected from C1-4 alkyl, phenyl, or halo.        Preferred Z includes 3-isopropyl-1,2,4-thiadiazol-5-yl,        thiazol-2-yl, 2,5-dimethyl-1,2-pyrazol-3-yl,        5-phenyl-1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-4-yl,        5-ethyl-1,3,4-thiadiazol-2-yl, 2-methyl-1,2-pyrazol-3-yl,        1,2,3,4-thiatriazol-5-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is absent or is C1-3 alkylene;    -   d. X₁ is absent or is O; and    -   e. T is selected from quinolinyl, preferably, quinolin-7-yl,        dihalo-substituted phenyl, preferably dichlorophenyl, or        naphthyl, preferably, 1-naphthyl.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z is selected from thiazol-2-yl, 1,3,4-thiadiazol-2-yl,        pyrimidin-2-yl, pyrimidin-2-yl, 1,2,4-triazol-3-yl, or        3-t-butyl-1,2-pyrazol-5-yl, optionally substituted with C1-4        alkyl, or benzyl;    -   b. R^(N) is hydrogen;    -   c. X₂ is absent or C1-4 alkylene or alkenylene;    -   d. X₁ is absent or O;    -   e. T is selected from phenyl, naphthyl,        2,2,-difluoro-benzo[1,3]dioxol-5-yl, norbornyl, indol-2-yl,        benzothiophen-3-yl, benzo[1,3]oxathiol-2-one-5-yl,        benzo[1,2,5]oxadiazol-5-yl, quinolinyl, or        1,2,3,4-tetralin-5-yl, optionally substituted with up to 3        substituents selected from halo, cyano, trifluoromethyl, C₁₋₄        alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, trifluoromethoxy, C(O)NH₂,        NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, C(O)C₁₋₄        alkyl, or 1-piperidyl.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z is selected from thiazol-2-yl,        5-methyl-1,3,4-thiadiazol-2-yl, pyrimidin-2-yl,        4-methyl-pyrimidin-2-yl, 1,2,4-triazol-3-yl, or        1-benzyl-3-t-butyl-1,2-pyrazol-5-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is absent or is C1-4 straight or branched alkylene or        alkenylene, optionally substituted with phenyl;    -   d. X₁ is absent or is O; and    -   e. T is selected from phenyl,        2,2,-difluoro-benzo[1,3]dioxol-5-yl, norbornyl, indol-2-yl,        benzothiophen-3-yl, benzo[1,3]oxathiol-2-one-5-yl,        benzo[1,2,5]oxadiazol-5-yl, quinolinyl, or        1,2,3,4-tetralin-5-yl, optionally substituted with up to 3        substituents selected from halo, cyano, trifluoromethyl, C₁₋₄        alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, trifluoromethoxy, C(O)NH₂,        NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄        alkyl.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z is selected from thiazol-2-yl,        5-methyl-1,3,4-thiadiazol-2-yl, pyrimidin-2-yl,        4-methyl-pyrimidin-2-yl, or 1,2,4-triazol-3-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is absent; or X₂ is C1-4 straight or branched alkyl;    -   d. X₁ is absent; or X₁ is O;    -   e. T is 2,6-dichlorophenyl, 3-diethyaminophenyl, 2-methyl,        4-fluorophenyl, 2-cyanophenyl, 2-ethoxyphenyl, 2-chlorophenyl,        4-cyanophenyl, 1-naphthyl, 5-methoxybenzofuran-2-yl,        6-chlorobenzofuran-2-yl, 2-methyl-5,7-dichloro-quinolin-8-yl,        2-piperidinyl-phenyl, 1,2,3,4-tetralin-6-yl,        2-dimethyl-4,7-dimethyl-1,2,3,4-tetrahydroquinolin-1-yl,        2,6-difluorophenyl, 3-fluorophenyl, 2-fluoro-3-chlorophenyl,        2,5-dimethylphenyl, 2,4-dichlorophenyl, 4-chlorophenyl,        2-fluoro-6-chlorophenyl, 3,5,-dimethyl-4-chlorophenyl,        3,5-difluorophenyl, 2,3-dichlorophenyl,        2-fluoro-3-methyl-6-chlorophenyl, isoquinolin-5-yl,        2,6-dimethoxyphenyl, 4-ethoxyphenyl, 5-fluoro-indol-2-yl,        2-methoxy-4-methylphenyl, 3-fluoro-5-trifluoromethylphenyl,        3-fluorophenyl, 1-methyl-5-chloro-indol-2-yl,        2,3-difluorophenyl, 8-methyl-1,2,3,4-tetrahydroquinolin-1-yl,        1,2,3,4-tetrahydroquinolin-1-yl, 2-trifluoromethoxyphenyl,        7-trifluoromethyl-1,2,3,4-tetrahydroquinolin-1-yl, or        2-chloro-3,5-difluorophenyl.

In certain embodiments, the present invention provides compounds offormula IIA-i, formula IIB-i, formula IIC-i, and formula IID-i:

wherein T is X₂, X₁, and T are as defined above.

According to another embodiment, the present invention provides acompound of formula III:

or a pharmaceutically acceptable salt thereof, wherein:

Z^(N) is a 5-7 membered monocyclic, unsaturated or aromatic,heterocyclic ring, having up to 4 heteroatoms independently selectedfrom O, N, NH, S, SO, or SO₂;

each R^(N) is independently hydrogen or C1-4 aliphatic optionallysubstituted with up to two substituents selected from R1, R4, or R5;

X₂ is C₁₋₃ aliphatic, optionally substituted with up to 2 substituentsindependently selected from R¹, R⁴, or R⁵;

T^(N) is a 3-14 membered monocyclic, bicyclic, or tricyclic, saturated,unsaturated, or aromatic ring system having up to 5 heteroatomsindependently selected from O, N, NH, S, SO, or SO₂;

wherein Z^(N) and T^(N) each is independently and optionally substitutedwith up to 4 substituents independently selected from R¹, R², R³, R⁴, orR⁵;

wherein the phenylene ring attached to the sulfonyl is optionallysubstituted with up to 3 substituents selected from R¹ and R²;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), R⁶ or (CH₂)_(n)—Y;

n is 0, 1 or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶; or

two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxyor 1,2-ethylenedioxy;

R² is aliphatic, wherein each R² is optionally substituted with up to 2substituents independently selected from R¹, R⁴, or R⁵;

R³ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring isoptionally substituted with up to 3 substituents, independently selectedfrom R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂,NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶,N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶),P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂,P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ringoptionally is optionally substituted with up to 3 R¹ substituents;

R⁶ is H or aliphatic, wherein R⁶ is optionally substituted with a R⁷substituent;

R⁷ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring and eachR⁷ is optionally substituted with up to 2 substituents independentlychosen from H, aliphatic, or (CH₂)_(n)-Z′;

Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo),—OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S-aliphatic, S(O)-aliphatic,SO₂-aliphatic, NH₂, NH-aliphatic, N(aliphatic)₂, N(aliphatic)R⁸, COOH,C(O)O(-aliphatic), or O-aliphatic; and

R⁸ is an amino protecting group.

In certain embodiments of formula III, the following compounds areexcluded:

a) when both R^(N) are hydrogen, then T^(N) is not:

-   -   (i) 1,3-dione-isoindol-2-yl, 1,3-dione-isoindol-2-yl substituted        with up to 4 halo substituents;

-   -    wherein R^(m) is methyl or phenyl optionally substituted with        up to 4 halo;

-   -    wherein W is O or S, and R^(o) is phenyl or substituted phenyl,    -   (iv) 4-methyl-1,4-dihydro-quinoxalin-1-yl,

(b) when both R^(N) are hydrogen, then the following compounds in TableC are excluded:

TABLE C Z^(N) X₂, together with T^(N)

wherein the asterisk denotes the point of attachment of a carbon atom tothe rest of the molecule.

In certain embodiments, Z^(N) is selected from:

In other embodiments, Z^(N) is selected from:

Preferably, Z^(N) is formula i-a.

In certain embodiments, Z^(N) is selected from:

In certain other embodiments, Z^(N) is selected from:

In yet other embodiments, Z^(N) is selected from:

Or, Z^(N) is selected from:

In certain embodiments, Z^(N) is selected from:

In other embodiments, Z^(N) is selected from:

In one embodiment, Z^(N) is as defined above for Z.

In certain embodiments, R^(N) is hydrogen. Or, R^(N) is unsubstitutedC1-4 alkyl.

In some embodiments, X₂ is selected from —CH₂—, —CH₂—CH₂—, —(CH₂)₃—,—CH(Me)—, —C(Me)═CH—, —CH═CH—, —CH(Ph)—, —CH₂—CH(Me)—, —CH(Et)-,—CH(i-Pr)—, or cyclopropylene.

Preferably, X₂ is selected from —CH₂—, —CH(Me)—, —CH₂—CH₂—, or —(CH₂)₃—.Or, X₂ is —CH₂—.

In certain embodiments, T^(N) is an optionally substituted, saturated,unsaturated, or aromatic 5-6 membered monocyclic ring. Preferably T^(N)is a 5-membered ring with up to 3 heteroatoms, preferably twoheteroatoms. Or, T^(N) is a 6-membered ring with up to 2 heteroatoms,preferably 1 heteroatom. In certain preferred embodiments, T^(N) has asecond heteroatom selected from O, S, N, or NH.

In other embodiments, T^(N) is an optionally substituted, saturated,unsaturated, or aromatic 8-12 membered bicyclic ring.

In other embodiments, T^(N) is selected from 1-pyrrolyl,2,3-dihydro-1H-pyrrol-1-yl, 1-pyrazolyl, 1-imidazolyl, 1-pyrrolidinyl,1,2,3,4-tetrahydropyrid-1-yl, 1,2,3,6-tetrahydropyrid-1-yl,1-piperidinyl, 1-piperazinyl, 1-morpholinyl, 1-azepinyl, 1-azepanyl,1-indolyl, 1-indolinyl, 1,2,3,4-tetrahydroquinolin-1-yl,1,2,3,4-tetrahydroisoquinolin-2-yl, wherein said ring is optionallysubstituted with up to 3 substituents. Preferably, T^(N) is fused to aphenyl ring, wherein said phenyl ring is optionally substituted with upto three substituents.

According to another embodiment, T^(N) is an optionally substituted ringselected from:

According to one embodiment, T^(N) is formula i or ii above, optionallysubstituted as provided above. Or, T^(N) is formula v or vi above,optionally substituted as provided above. Or, T^(N) is formula vii,optionally substituted as provided above.

According to another embodiment, T^(N) is an optionally substituted ringselected from:

According to another embodiment, T^(N) is any of the above rings viii toxxiii, optionally fused to an optionally substituted phenyl ring.

According to another embodiment, T^(N) is any of the above rings viii toxxiii, optionally fused to an optionally substituted 6-membered aromaticheterocyclic ring having up to 3 nitrogen atoms. Preferred such6-membered rings include pyridyl, pyrimidinyl, pyrazyl, or pyridazinyl.

According to another embodiment, T^(N) is an optionally substituted ringselected from:

According to another embodiment, T^(N) is any of the above rings xxiiito xxx, optionally fused to an optionally substituted phenyl ring.

According to another embodiment, T^(N) is any of the above rings xxiiito xxx, optionally fused to an optionally substituted 6-memberedaromatic heterocyclic ring having up to 3 nitrogen atoms. Preferred such6-membered rings include pyridyl, pyrimidinyl, pyrazyl, or pyridazinyl.

Preferred substituents on T^(N) are independently selected from halo,cyano, trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

In one embodiment, the phenylene ring attached to the sulfonyl group isoptionally substituted with up two substituents selected from halo,cyano, trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z^(N) is thiazol-2-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is C1-4 alkylene, preferably, —CH₂— or —CH₂—CH₂—; and    -   d. T^(N) is selected from indol-1-yl,        1,2,3,4-tetrahydroquinolin-1-yl, indolin-1-yl,        1,2,3,4-tetrahydroisoquinolin-2-yl, or        5-benzylidene-thiazolidin-2,4-dione-3-yl, optionally substituted        with up to three substituents independently selected from C1-4        alkyl, C1-4 alkoxy, halo, trifluoromethyl, or cyano.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z^(N) is thiazol-2-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is C1-4 alkylene, preferably, —CH₂— or —CH₂—CH₂—; and    -   d. T^(N) is selected from 4-fluoro-indol-1-yl,        6-chloro-indol-1-yl, 6-chloro-1,2,3,4-tetrahydroquinolin-1-yl,        5-ethyl-indol-1-yl, 4-fluoro-indol-1-yl, indol-1-yl,        5-methyl-indol-1-yl, 5-fluoro-indolin-1-yl, 7-chloro-indol-1-yl,        1,2,3,4-tetrahydroquinolin-1-yl,        1,2,3,4-tetrahydroisoquinolin-2-yl,        6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl,        2-methyl-indolin-1-yl, 5-chloro-indolin-1-yl,        6-methyl-1,2,3,4-tetrahydroquinolin-1-yl,        5,6-dimethoxy-indol-1-yl,        1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl,        6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl,        5-fluoro-6-chloro-indol-1-yl, 4-methyl-indol-1-yl,        4-chloro-6-methoxy-indol-1-yl, 2-methyl-indol-1-yl,        2,3-dimethyl-indol-1-yl, or        5-(4′-fluoro-benzylidene)-3-methyl-thiazolidin-2,4-dione-3-yl.

In one embodiment, the present invention provides compounds wherein:

-   -   a. Z^(N) is thiazol-2-yl;    -   b. R^(N) is hydrogen;    -   c. X₂ is C1-3 alkylene, preferably —CH₂—;    -   d. T^(N) is selected from indol-1-yl,        1,2,3,4-tetrahydroisoquinolin-2-yl, 5-methyl-indol-1-yl,        6-chloroindolin-1-yl, 6-chloro-indol-1-yl, 6-fluoro-indol-1-yl,        6-chloro-1,2,3,4-tetrahydroquinolin-1-yl, 4-fluoro-indol-1-yl,        5-fluoro-indol-1-yl, 4,4-difluoropiperidinyl,        5-cyano-indol-1-yl, 5-ethyl-indol-1-yl,        1,2,3,4-tetrahydroquinolin-1-yl, 6-trifluoromethyl-indol-1-yl,        5,6-dimethoxy-indol-1-yl,        6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl, 5-chloroindolin-1-yl,        1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl, 3-cyano-indol-1-yl,        3-methyl-indol-1-yl, 2-methyl-6-fluoro-quinolin-4-yl,        5-methoxy-benzofuran-2-yl, 4-methyl-indol-1-yl,        5,6-dichloro-indol-1-yl, 6-methylindol-1-yl,        4,6-dichloroindol-1-yl, 4-methoxy-indol-1-yl,        5-methoxy-indol-1-yl, 7-fluoro-indol-1-yl,        5-fluoro-indolin-1-yl,        5-(4′-fluoro-benzylidene)-1,3-thiolan-2,4-dione-3-yl,        2,3-dimethyl-indol-1-yl,        7-trifluoromethyl-1,2,3,4-tetrahydroquinolin-1-yl,        6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl, 7-ethyl-indol-1-yl,        or 2,7-dimethyl-1,2,3,4-tetrahydroquinolin-1-yl.

According to another embodiment, the present invention provides acompound of formula IV:

or a pharmaceutically acceptable salt thereof;

wherein:

Z^(M) is a 5-7 membered monocyclic, unsaturated or aromatic,heterocyclic ring, having up to 4 heteroatoms independently selectedfrom O, N, NH, S, SO, or SO₂;

each R^(N) is independently hydrogen or C1-4 aliphatic optionallysubstituted with up to two substituents selected from R1, R4, or R5;

X₁ is O, S, or NR^(N);

X₂ is C₁₋₃ aliphatic, optionally substituted with up to 2 substituentsindependently selected from R¹, R⁴, or R⁵;

T^(M) is a 8-14 membered aromatic or non-aromatic bicyclic or tricyclicring, having 0-5 heteroatoms selected from O, S, N, NH, S(O) or SO₂;

wherein the phenylene ring attached to the sulfonyl is optionallysubstituted with up to 3 substituents selected from R¹ and R²;

wherein Z^(M) and T^(M) each is independently and optionally substitutedwith up to 4 substituents independently selected from R¹, R², R³, R⁴, orR⁵;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), R⁶ or (CH₂)_(n)—Y;

n is 0, 1 or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶; or

two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxyor 1,2-ethylenedioxy;

R² is aliphatic, wherein each R² is optionally substituted with up to 2substituents independently selected from R¹, R⁴, or R⁵;

R³ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring isoptionally substituted with up to 3 substituents, independently selectedfrom R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂,NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶,N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶),P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂,P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring isoptionally substituted with up to 3 R¹ substituents;

R⁶ is H or aliphatic, wherein R⁶ is optionally substituted with a R⁷substituent;

R⁷ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring and eachR⁷ is optionally substituted with up to 2 substituents independentlychosen from H, aliphatic, or (CH₂)_(n)-Z′;

Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo),—OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S-aliphatic, S(O)-aliphatic,SO₂-aliphatic, NH₂, NH-aliphatic, N(aliphatic)₂, N(aliphatic)R⁸, COOH,C(O)O(-aliphatic), or O-aliphatic; and

R⁸ is an amino protecting group.

In one embodiment of formula IV, the following compounds are excluded:

(a) when Z is optionally substituted pyrimidinyl or thiazolyl, both R⁶are hydrogen, and X1 is NH, then T is not optionally substitutedadamantyl;

(b) when Z is optionally substituted pyridyl, pyrimidinyl, isoxazolyl,or thiazolyl, both R₆ are hydrogen, and X₁ is NH, then T is not

optionally substituted with up to two halo atoms;

(c) when both R₆ are hydrogen, and X₁ is NH, then T is not 1-naphthyl,2-naphthyl, or 7-hydroxynaphth-1-yl;

(d) when Z is pyrimidinyl, 5-methylisoxazolyl, or pyridyl, both R₆ arehydrogen, and X₁ is NH, then T is not substituted purinyl; and

(e) when Z is thiazol-2-yl, both R₆ are hydrogen, and X₁ is NH, then Tis not substituted 3H-isobenzofuran-1-one-7-yl.

In one embodiment, X¹ is O. Or, X¹ is S. Or X1 is NR^(N).

In one embodiment, each R^(N) is independently hydrogen. Or, each R^(N)is independently C1-4 alkyl.

In certain embodiments, Z^(M) is selected from:

In other embodiments, Z^(M) is selected from:

Preferably, Z^(M) is formula i-a.

In other embodiments, Z^(M) is selected from:

In yet other embodiments, Z^(M) is selected from:

Or, Z^(M) is selected from:

In certain embodiments, Z^(M) is selected from:

In certain other embodiments, Z^(M) is selected from:

Or, Z^(M) is selected from:

In one embodiments, Z^(M) is as defined above for Z.

In certain embodiments, R^(N) is hydrogen. Or, R^(N) is unsubstitutedC1-4 alkyl.

In another embodiment, Z^(M) is an optionally substituted 5-6 memberedmonocyclic ring.

In one embodiment, X₁ is NH. Or, X₁ is O.

In certain embodiments, T^(M) is phenyl or naphthyl, optionallysubstituted with up to 3 substituents independently selected from halo,cyano, trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, orC(O)C₁₋₄ alkyl.

In other embodiments, T^(M) is selected from:

wherein T^(M) is optionally substituted with up to three substituentsindependently selected from halo, cyano, trifluoromethyl, OH, C₁₋₄alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, trifluoromethoxy, C(O)NH₂, NH₂,NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

Or, T^(M) is selected from:

wherein T^(M) is optionally substituted with up to three substituentsindependently selected from halo, cyano, trifluoromethyl, OH, C₁₋₄alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, trifluoromethoxy, C(O)NH₂, NH₂,NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NHC(O)CO₁₄ alkyl, or C(O)C₁₋₄ alkyl.

Or, T^(M) is a tricyclic ring selected from: dibenzofuranyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, fluorenyl,anthracenyl, or phenoxazinyl.

In certain embodiments, the substituents are independently selected fromoxo, halo, cyano, trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

In one embodiment of formula (IIA-i):

-   -   a. X₂ is —CH₂—, —CH₂—CH₂— or —CH₂CH₂CH₂—;    -   b. X₁ is O or S; and    -   c. T is selected from 8-trifluoromethylquinolin-4-yl,        3-chloro-4-fluorophenyl, 1-naphthyl, 4-chloro-3-fluorophenyl,        6-fluoro-2-methyl-quinolin-4-yl, 2,4-dichlorophenyl,        4-chlorophenyl, 2,3-difluorophenyl, 2-chloro-4-methoxyphenyl,        4-trifluoromethylphenyl, 4-chloro-2-fluorophenyl,        benzo[1,3]oxathiol-2-one-6-yl, 1-phenyl-tetrazol-5-yl,        benzo[1,2,5]oxadiazol-5-yl,        3-cyano-5,6,7,8-tetrahydroquinolin-2-yl, quinolin-2-yl,        isoquinolin-5-yl, quinolin-7-yl, or 3,5-dimethyl-4-cyanophenyl.

In one embodiment of formula (IIB-i):

-   -   a. X₂ is —CH₂—, —CH₂—CH₂—, —CH₂CH₂CH₂—, or —CH═CH—;    -   b. T is selected from benzo[b]thiophen-3-yl,        5-chloro-benzo[b]thiophen-2-yl,        5-chloro-2,3-dihydro-1H-indol-1-yl,        5-fluoro-2,3-dihydro-1H-indol-1-yl,        8-methoxy-1,2,3,4-tetrahydronaphth-2-yl,        1,2,3,4-tetrahydroquinolin-1-yl,        6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl,        2,3-dihydro-1H-indol-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl,        2-methyl-2,3-dihydro-1H-indol-1-yl,        6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl, or 3-(t-butylamino        carbonyl)-1,2,3,4-tetrahydro isoquinolin-2-yl.

In one embodiment of formula (IIC-i), T is selected from4,6-dichloroindol-2-yl, benzofuran-2-yl, 1-naphthyl,2-methyl-6-fluoroquinolin-4-yl, 5-fluoro-indol-2-yl,5-chlorothiophen-2-yl, benzopyran-3-yl, 3-bromo-4-methylphenyl,2-(furan-2-yl)-quinolin-4-yl, N-methyl-5-trifluoromethoxy-indol-2-yl,benzothiophen-3-yl, 5-fluoro-benzothiophen-2-yl, 2-methyl-quinolin-4-yl,6-chloro-indol-2-yl, 6-bromo-indol-2-yl,2-phenyl-5-methyl-1,2-oxazol-3-yl, N,6-dimethyl-indol-2-yl, or5-3,5,dichlorophenoxy-furan-2-yl.

In one embodiment of formula (IIA-i):

-   -   a. X₂ is CH₂, —CH₂CH₂, or CH₂CH₂CH₂;    -   b. X₁ is O, S, or NH; and    -   c. T is phenyl optionally substituted with up to three        substituents selected from halo, cyano, trifluoromethyl, OH,        C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C1-4        alkyl), N(C1-4 alkyl)₂, NHC(O)C1-4 alkyl, 1-pyrrolidinyl,        1-piperidinyl, 1-morpholinyl, or C(O)C₁₋₄ alkyl.

In one embodiment, X₁ is O. Or, X₁ is S. Or, X₁ is NH.

In one embodiment of formula (IIIA-i):

-   -   a. X₂ is CH₂, —CH₂CH₂, or CH₂CH₂CH₂;    -   b. X₁ is O, S, or NH; and    -   c. T is quinolin-4-yl, quinolin-5-yl, quinolin-6-yl,        quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, 1-naphthyl,        2-naphthyl, 5a,6,7,8,9,9a-hexahydro-dibenzofuran-2-yl,        benzo[1,3]dioxol-6-yl, benzothiazol-5-yl, indan-1-one-4-yl,        benzo[1,2,5]oxadiazol-4-yl, indol-4-yl,        4-methyl-chromen-2-one-7-yl, indol-5-yl,        benzo-[1,2,3]-triazin-4-yl, or benzimidazol-2-yl, wherein T is        optionally substituted with up to three substituents selected        from halo, cyano, trifluoromethyl, OH, C1-4 alkyl, C1-4 alkoxy,        trifluoromethoxy, C(O)NH₂, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2,        NHC(O)C1-4 alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl,        or C(O)C1-4 alkyl.

In another embodiment of formula (IIIA-i):

-   -   a. X₂ is CH₂, —CH₂CH₂, or CH₂CH₂CH₂;    -   b. X₁ is O, S, or NH; and    -   c. T is quinolin-5-yl, 2-naphthyl,        5a,6,7,8,9,9a-hexahydro-dibenzofuran-2-yl,        benzo[1,3]dioxol-6-yl, 8-fluoroquinolin-4-yl,        2-methyl-benzothiazol-5-yl, 7-trifluoromethyl-quinolin-4-yl,        indan-1-one-4-yl, benzo[1,2,5]oxadiazol-4-yl, isoquinolin-1-yl,        indol-4-yl, 5,7-dichloro-2-methylquinolin-8-yl,        7-chloro-quinolin-4-yl, 4-methyl-chromen-2-one-7-yl,        quinolin-8-yl, 5-chloro-quinolin-8-yl, indol-5-yl,        quinolin-6-yl, benzo-[1,2,3]-triazin-4-yl,        7-fluoro-quinolin-4-yl, benzimidazol-2-yl, or        2-methyl-quinolin-8-yl.

According to an alternate embodiment, the present invention provides acompound having formula (V):T₁--L₁₁-A--L₂₂-Z;

-   -   wherein:    -   T₁ is a 8-14 membered aromatic or non-aromatic bicyclic or        tricyclic ring, having 0-5 heteroatoms selected from O, S, N,        NH, S(O) or SO₂;

L₁₁ is —(X₁)_(p)—(CHR¹)_(r)—(X₂)—Ry;

-   -   wherein:        -   p is 0 or 1;        -   r is 0 or 1;        -   X₁ is O, S, or NR_(x), wherein R_(x) is H or R₂;        -   X₂ is R²;        -   Ry is —C(O)—NR²—;

L₂₂ is OC(O), C(O)O, S(O), SO₂, N(R⁵)SO₂, N(R⁶)SO₂, SO₂N(R⁵), SO₂N(R⁶),C(O)N(R⁵), C(O)N(R⁶), NR⁵C(O), NR⁶C(O), C(NOR⁵)R⁶, C(NOR⁵)R⁶, C(NOR⁶)R⁵,C(NOR⁶)R⁶, N(R⁵), N(R⁶), NR⁵C(O)O, NR⁶C(O)O, OC(O)NR⁵, OC(O)NR⁶,NR⁵C(O)N(R⁵), NR⁵C(O)N(R⁶), NR⁶C(O)N(R⁵), NR⁶C(O)N(R⁶), NR⁵SO₂N(R⁵),NR⁵SO₂N(R⁶), NR⁶SO₂N(R⁵), NR⁶SO₂N(R⁶), N(OR⁵), or N(OR⁶);

A is a 5-7 membered monocyclic aromatic ring, having 0-4 heteroatoms;

Z is 2-thiazolyl;

wherein each of T₁, A, and Z is optionally substituted with up to 4suitable substituents independently selected from R¹, R², R³, R⁴, or R⁵;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), R⁶ or (CH₂)_(n)—Y;

n is 0, 1 or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶; or

two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxyor 1,2-ethylenedioxy;

R² is aliphatic, wherein each R² is optionally substituted with up to 2substituents independently selected from R¹, R⁴, or R⁵;

R³ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring isoptionally substituted with up to 3 substituents, independently selectedfrom R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶; C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂,NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶,N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶),P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂,P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring isoptionally substituted with up to 3 R¹ substituents;

R⁶ is H or aliphatic, wherein R⁶ is optionally substituted with a R⁷substituent;

R⁷ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring and eachR⁷ is optionally substituted with up to 2 substituents independentlychosen from H, aliphatic, or (CH₂)_(n)-Z;

Z is selected from halo, CN, NO₂, CF₃, OCF₃. OH, S-aliphatic,S(O)-aliphatic, SO₂-aliphatic, NH₂, N-aliphatic, N(aliphatic)₂,N(aliphatic)R⁸, COOH, C(O)O(-aliphatic, or O-aliphatic; and

R⁸ is an amino protecting group.

In one embodiment of formula V:

(i) when:

-   -   L₂₂ is SO₂, N(R⁵)SO₂, N(R⁶)SO₂, SO₂N(R⁵), SO₂N(R⁶), C(O)N(R⁵),        C(O)N(R⁶), NR⁵C(O), or NR⁶C(O);    -   A is optionally substituted 5-6 membered monocyclic aromatic        ring with 0-4 heteroatoms independently selected from N, S, or        O;    -   X₂ is optionally substituted methylene or ethylene;    -   T₁ is an optionally substituted fused aromatic bicyclic ring        system containing 0-4 heteroatoms independently selected from N,        O, or S;

then:

-   -   r is 1;

(ii) when:

-   -   L₂₂ is SO₂, N(R⁵) SO₂, N(R⁶) SO₂, SO₂N(R⁵), SO₂N(R⁶), C(O)N(R⁵),        C(O)N(R⁶), NR⁵C(O), or NR⁶C(O);    -   A is optionally substituted 5-6 membered monocyclic aromatic        ring with 0-4 heteroatoms independently selected from N, S, or        O;    -   p is 1;    -   X₂ is optionally substituted methylene, ethylene, or propylene;    -   T₁ is an optionally substituted fused aromatic bicyclic ring        system containing 0-4 heteroatoms independently selected from N,        O, or S;

then:

-   -   X₁ is not O or S;

(iii) when:

-   -   L₁₁ is —O—CH₂—C(O)—NH—;    -   A is phenylene;    -   L₂₂ is —S(O)₂—NH—;    -   then:    -   T₁ is not any of the following:

(iv) when:

-   -   L₁₁ is —S—CH₂—C(O)—NH—;    -   A is phenylene;    -   L₂₂ is —S(O)₂—NH—;    -   then:    -   T₁ is not any of the following:

wherein B is hydrogen, methyl, n-propyl, isopropyl, allyl, benzyl, orphenylethyl.

Preferred embodiments of L₁₁, L₂₂, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ informula (V) are as described above for formula (I).

According to a preferred embodiment, Ry is —C(O)—NR²—.

According to a preferred embodiment, T₁ is a 8-14 membered aromatic ornon-aromatic bicyclic or tricyclic ring, having 0 heteroatoms. Morepreferably, T₁ is naphthyl. Or, T₁ is anthracenyl. According to analternate more preferred embodiment, T₁ is tetralinyl or decalinyl.

According to a preferred embodiment, T₁ is a 8-14 membered aromatic ornon-aromatic bicyclic or tricyclic ring, having up to 5 heteroatoms,preferably 1 or 2 heteroatoms. More preferably, T₁ is a 8-14 memberedaromatic bicyclic ring, having up to 5 heteroatoms. Or, T₁ is a 8-14membered non-aromatic bicyclic ring, having up to 5 heteroatoms.Exemplary bicyclic rings include quinolinyl, isoquinolinyl,benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, benzofuranyl,benzothiophenyl, indolizinyl, indolyl, isoindolyl, indolinyl, indazolyl,benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, phthalazine,quinazolinyl, quinaoxalinyl, naphthylirinyl, or pteridinyl.

According to another preferred embodiment, T₁ is a 8-14 memberednon-aromatic tricyclic ring, having up to 5 heteroatoms. Or, T₁ is a8-14 membered aromatic tricyclic ring, having up to 5 heteroatoms.Exemplary tricyclic rings include dibenzofuranyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, acridinyl, phenazinyl,phenothiazinyl, phenoxainyl, or carbazolyl.

According to a preferred embodiment of formula (II), A is phenyl.

According to another preferred embodiment of formula (II), A is a 5-6membered monocyclic aromatic ring having 1-4 heteroatoms. Morepreferably, A is 5-6 membered monocyclic aromatic ring having 1-3heteroatoms. Exemplary rings include thiazolyl, isothiazolyl,thiadiazolyl, thiaphenyl, furanyl, oxazolyl, isooxazolyl, oxadiazolyl,triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, or pyrrolyl.

FIG. 1 recites exemplary compounds of the present invention.

The compounds of the present invention may be readily prepared bymethods well known in the art. An exemplary method for synthesizingcertain compounds of formula (I) is illustrated below in the schemes.

In Scheme 1 above, the synthesis of compounds of formula (I), wherein Ryis an amide (—C(O)—NH—) is illustrated. Compound of formula (AA) iscoupled with an amine of formula (BB), wherein T₁, X₁, X₂, p, q, A, L₂,and Z have the meaning as defined in formula (I). LG is any suitableleaving group. Suitable leaving groups useful in the method of Scheme 1are well known in the art. See, e.g., “March's Advanced OrganicChemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March, J., John Wiley &Sons, New York: 2001.

Reaction of i and ii (step a) in pyridine and DCM at room temperature(rt) yields IA.

The coupling of i and ii (step a) using CDI and DMA under refluxingconditions, or HATU and TEA in pyridine under microwave conditions at200° C., or BOP and TEA in CH₃CN at rt yields IA.

In the schemes below, R⁶ is as defined for R^(N).

The coupling of i with anilines (step a) using CDI and DMA underrefluxing conditions, or HATU and TEA in pyridine under microwaveconditions at 200° C., or isobutyl chlorocarbonate and TEA in DCM yieldsii. Reaction of intermediate ii with ClSO₃H (step b) under refluxingconditions gives iv. Reaction of ii ClSO₃H at 0° C. (step c) givesintermediate iii. Coupling of intermediate i with aminosulfonic acids(step d) using HATU and TEA in pyridine under microwave conditions at200° C., or BOP and TEA in CH₃CN at rt yields iii. Reaction ofintermediate iii with SO₂C1 (step e) yields iv. Alternatively, reactionof intermediate iii with cyanuric chloride and TEA in acetone undermicrowave conditions at 120° C. (step e) provides iv. Reaction of ivwith various amines (step f) in pyridine at room temperature yields IA.

The reaction of intermediate i with amines (step a) in pyridine at rtyields ii. Reaction of intermediate ii with tin in 10% HCl (step b)under refluxing conditions gives iii. Reaction of iv with amines (stepc) in pyridine, followed by treatment with 10% NaOH provides iii.

Reaction of i and ii (step a) in pyridine and DCM at rt yields iv. Thecoupling of i and iii (step b) using CDI and DMA under refluxingconditions, or HATU and TEA in pyridine under microwave conditions at200° C., or BOP and TEA in CH₃CN at rt yields iv. The reaction of iv andv (step c) under alkylation conditions provides IIA. These alkylationconditions include NaH and K₂CO₃ as bases, DMF, DMSO, and THF assolvents, under rt, microwave, and reflux conditions.

The reaction of i and ii (step a) under alkylation conditions providesintermediate iii. These alkylation conditions include NaH and K₂CO₃ asbases, and NaI can be added. Solvents include DMF, DMSO, and THF, andreaction conditions include rt, microwave, and refluxing conditions. Thereaction of i and ii (step c) in H₂O and NaOH provides intermediate iv.The reaction of intermediate iii (step b) using 2N NaOH, or H₂O in DMAunder microwave conditions yields iv. Treatment of iv with oxalylchloride or thionyl chloride provides v.

The coupling of i and ii (step a) using CDI and DMA under refluxingconditions, or HATU and TEA in pyridine under microwave conditions at200° C., or BOP and TEA in CH₃CN at rt yields IIB. Reaction of i and iii(step a) in pyridine and DCM at rt yields IIB.

The coupling of i with anilines (step a) using CDI and DMA underrefluxing conditions, or HATU and TEA in pyridine under microwaveconditions at 200° C., or isobutyl chlorocarbonate and TEA in DCM yieldsii. Reaction of intermediate ii with ClSO₃H (step b) under refluxingconditions gives iv. Reaction of ii ClSO₃H at 0° C. (step c) givesintermediate iii. Coupling of intermediate i with aminosulfonic acids(step d) using HATU and TEA in pyridine under microwave conditions at200° C., or BOP and TEA in CH₃CN at rt yields iii. Reaction ofintermediate iii with SO₂Cl (step e) yields iv. Alternatively, reactionof intermediate iii with cyanuric chloride and TEA in acetone undermicrowave conditions at 120° C. (step e) provides iv. Reaction of ivwith various amines (step f) in pyridine at room temperature yields IIB.

The coupling of i and ii (step a) using CDI and DMA under refluxingconditions, or HATU and TEA in pyridine under microwave conditions at200° C., or BOP and TEA in CH₃CN at rt yields IIC. Reaction of i and iii(step a) in pyridine and DCM at rt yields IIC.

The coupling of i with anilines (step a) using CDI and DMA underrefluxing conditions, or HATU and TEA in pyridine under microwaveconditions at 200° C., or isobutyl chlorocarbonate and TEA in DCM yieldsii. Reaction of intermediate ii with ClSO₃H (step b) under refluxingconditions gives iv. Reaction of ii ClSO₃H at 0° C. (step c) givesintermediate iii. Coupling of intermediate i with aminosulfonic acids(step d) using HATU and TEA in pyridine under microwave conditions at200° C., or BOP and TEA in CH₃CN at rt yields iii. Reaction ofintermediate iii with SO₂C1 (step e) yields iv. Alternatively, reactionof intermediate iii with cyanuric chloride and TEA in acetone undermicrowave conditions at 120° C. (step e) provides iv. Reaction of ivwith various amines (step f) in pyridine at room temperature yields IIB.

The reaction of intermediate i with 20% diphosgene and TEA (step a) inPhCH₃ with heating provides ii. The treatment of ii with iii (step b)yields IID.

The reaction of intermediate i with ii in TEA/CH₃CN (step a) providescompounds IID.

The reactions of intermediate i and ii (step a) in THF at rt providesintermediate iii. The treatment of intermediate iii with various amines(step b) in yridines at rt provides IID.

The reaction of i and ii (step a) under alkylation conditions providesIII. These alkylation conditions include NaH and K₂CO₃ as bases, and NaIcan be added. Solvents include DMF, DMSO, and THF, and reactionconditions include rt, microwave, and refluxing conditions.

One of skill in the art will appreciate that in addition to the aboveschemes, analogous methods known in the art may be readily used tosynthesize other compounds of the present invention.

As discussed above, the present invention provides compounds that areinhibitors of voltage-gated sodium ion channels, and thus the presentcompounds are useful for the treatment of diseases, disorders, andconditions including, but not limited to acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsyconditions, neurodegenerative disorders, psychiatric disorders such asanxiety and depression, myotonia, arrythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, and incontinence. Accordingly, in another aspect of thepresent invention, pharmaceutically acceptable compositions areprovided, wherein these compositions comprise any of the compounds asdescribed herein, and optionally comprise a pharmaceutically acceptablecarrier, adjuvant or vehicle. In certain embodiments, these compositionsoptionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative which uponadministration to a patient in need is capable of providing, directly orindirectly, a compound as otherwise described herein, or a metabolite orresidue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium ion channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome, orincontinence is provided comprising administering an effective amount ofa compound, or a pharmaceutically acceptable composition comprising acompound to a subject in need thereof. In certain preferred embodiments,a method for the treatment or lessening the severity of acute, chronic,neuropathic, or inflammatory pain is provided comprising administeringan effective amount of a compound or a pharmaceutically acceptablecomposition to a subject in need thereof. In certain embodiments of thepresent invention an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective fortreating or lessening the severity of one or more of acute, chronic,neuropathic, or inflammatory pain, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome, orincontinence.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, epilepsyor epilepsy conditions, neurodegenerative disorders, psychiatricdisorders such as anxiety and depression, myotonia, arrythmia, movementdisorders, neuroendocrine disorders, ataxia, multiple sclerosis,irritable bowel syndrome, or incontinence. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “patient”, as used herein, means ananimal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar—agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in a proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels or calcium channels,preferably N-type calcium channels. In one embodiment, the compounds andcompositions of the invention are inhibitors of one or more of NaV1.1,NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, orCaV2.2, and thus, without wishing to be bound by any particular theory,the compounds and compositions are particularly useful for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3,NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,NaV1.9, or CaV2.2, is implicated in a particular disease, condition, ordisorder, the disease, condition, or disorder may also be referred to asa “NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 orNaV1.9-mediated disease, condition or disorder” or a “CaV2.2-mediatedcondition or disorder”. Accordingly, in another aspect, the presentinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity of oneor more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9,or CaV2.2 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

In certain exemplary embodiments, compounds of the invention are usefulas inhibitors of NaV1.8. In other embodiments, compounds of theinvention are useful as inhibitors of NaV1.8 and CaV2.2. In still otherembodiments, compounds of the invention are useful as inhibitors ofCaV2.2.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

Examples of additional agents opiois, COX-2 inhibitors, localanesthestics, tricyclic antidepressants, NMDA modulators, cannibaloidreceptor agonists, P2X family modulators, VR1 antagonists, and substanceP antagonists.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 NaV1.9, or CaV2.2activity in a biological sample or a patient, which method comprisesadministering to the patient, or contacting said biological sample witha compound of formula I or a composition comprising said compound. Theterm “biological sample”, as used herein, includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Inhibition of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample is useful fora variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, the study ofsodium ion channels in biological and pathological phenomena; and thecomparative evaluation of new sodium ion channel inhibitors.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES 4-(2,4-Dichloro-phenoxy)-butyric acid ethyl ester

To a mixture of 2,4-dichlorophenol (32.6 g, 0.2 mol), NaI (3 g) andK₂CO₃ (69 g, 0.5 mol) in DMF (500 mL) was added dropwise ethyl4-bromobutyrate (39 g, 0.2 mol) at 80° C. The reaction mixture wasstirred at 80° C. for 2 h until the reaction mixture turned tocolorless. The cooled mixture was filtered and the filtrate was dilutedwith EtOAc (1000 mL), washed with water (3×500 mL), dried, andconcentrated to give the crude butyrate (57 g) as colorless oil. ¹H-NMR(CDCl₃): δ 7.34 (d, 1H, J=8.8 Hz), 7.16 (dd, 1H, J₁=8.8 Hz, J₂=2.4 Hz),6.84 (d, 1H, J=8.8 Hz), 4.15 (q, 2H, J=7.2 Hz), 4.06 (t, 2H, J=7.2 Hz),2.54 (t, 2H, J=7.2 Hz), 2.17 (p. 2H, 6.4), 1.25 (t, 3H, J=7.2 Hz).

4-(2,4-Dichloro-phenoxy)-butyric acid

To a solution of ethyl 4-(2,4-dichlorophenoxy)-butyrate (57 g, crudefrom last step, about 0.2 mol) in THF (500 mL) and water (500 mL) wasadded LiOH.H₂O (12.6 g, 0.3 mol), and the reaction mixture was stirredfor 5 h at RT. The mixture was washed with Et₂O (3×200 mL), and theaqueous layer was acidified by addition of HCl (20%) to pH ˜2. Themixture was extracted with EtOAc (3×400 mL), the combined organicextracts were washed with water and brine, dried over Na₂SO₄ andconcentrated in vacuo to give the butyric acid (37 g, 74.3% from2,4-dichlorophenol) as a white solid. ¹H-NMR (CDCl₃): δ 7.36 (d, 1H,J=8.8 Hz), 7.18 (dd, 1H, J₁=8.8 Hz, J₂=2.4 Hz), 6.84 (d, 1H, J=8.8 Hz),4.07 t, 2H, J=7.2 Hz), 2.64 (t, 2H, J=7.2 Hz), 2.17 (p, 2H, J=6.4 Hz).

4-(2,4-dichlorophenoxy)-N-phenylbutyramide

To a solution of the 4-(2,4-dichloro-phenoxy)-butyric acid (9.8 g, 40mmol) and triethylamine (6.0 ml, 40 mmol) in dichloromethane (150 mL)was added dropwise isobutyl chlorocarbonate (6 mL, 40 mol) at −30° C.After stirring at −30° C. for 3 h, aniline (4 mL 40 mol) was addeddropwise. The reaction mixture was stirred for 3 h at −30° C. and thenallowed to warm up to RT. Aqueous HCl (5%, 100 mL) was added andstirring was continued for 0.5 h. The phases were separated, the aqueouslayer was extracted with dichloromethane (2×200 mL). The combinedorganic extracts were washed with water and brine, dried over Na₂SO₄ andconcentrated in vacuo to give the product (10 g, 77.5%). ¹H-NMR (CDCl₃):δ 7.49 (d, 2H, J=8.0 Hz), 7.38 (d, 1H, J=2.4 Hz), 7.31 (t, 2H, J=8.0Hz), 7.18 (dd, 1H, J₁=8.8 Hz, J₂=2.4 Hz) 7.12 (t, 1H, J=8.0), 6.87 (d,1H, J=8.8 Hz), 4.12 (t, 2H, J=6.4 Hz), 2.64 (t, 2H, J=6.4 Hz), 2.25 (p,2H, J=6.4 Hz)

4-[4-(2,4-Dichlorophenoxy)-butyrylamino]-benzenesulfonyl chloride

To a solution of 4-(2,4-dichlorophenoxy)-N-phenyl-butyramide (9.8 g, 30mmol) in chloroform (100 mL) was added chlorosulfonic acid (11.6 g, 100mmol). The reaction mixture was stirred at RT for 36 h, then water (200mL) was added to quench the reaction. The mixture was extracted withEtOAc (3×200 mL), the combined organic extracts were washed with waterand brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by chromatography over silica to give the sulfonyl chloride(3.5 g, 32%) as a white solid: ¹H-NMR (CDCl₃): δ 7.97 (d, 2H, J=8.8 Hz),7.75 (d, 2H, J=8.8 Hz), 7.63 (br, s, 1H), 7.37 (d, 1H, J=2.4 Hz), 7.21(dd, 1H, J₁=8.8 Hz, J₂=2.4 Hz), 6.87 (d, 1H, J=8.8 Hz), 4.12 (t, 2H,J=5.6 Hz), 2.72 (t, 2H, J=6.8 Hz), 2.31 (p, 2H, J=6.4 Hz).

4-(2,4-Dichloro-phenoxy)-N-[(4-[1,2,4]thiadiazol-5-ylsulfamoyl)-phenyl]butyramide

To a solution of the sulfonyl chloride (84 mg, 0.2 mmol) in pyridine (1mL) was added 5-amino-1,2,4-thiazole (40 mg, 0.4 mmol) and the reactionmixture stirred at rt for 24 h. The reaction mixture was quenched with50% DMSO and MeOH (3 mL) and purified by HPLC (gradient 10-99%CH₃CN/water). LC/MS (10-99%) M/Z: M⁺1 obs=487.0; t_(R)=3.23 min.

5,7-Dichloro-1H-indol-2-carboxylic acid[4-(thiazol-2-ylsulfamoyl)-phenyl]-amide

To a solution of 5,7-dichloro-indole-2-carbonylchloride (186 mg, 0.75mmol) in pyridine (0.8 mL, 1 mmol) and DCM (5.2 mL) was addedN′-(2-thiazolyl)sulfanilamide (128 mg, 0.5 mmol) and the reactionmixture stirred at rt for 16 h. The resulting solid was filtered, washedwith DCM (3×5 mL), and dried under vacuum overnight to provide theproduct (0.21 g; yield=90%) as a white-green solid. ¹H-NMR (DMSO-d₆)12.78 (s, 1H), 12.33 (s, 1H), 10.67 (s, 1H), 7.97 (d, J=7.0 Hz, 2H),7.82 (d, J=7.0 Hz, 2H), 7.62 (d, J=1.5 Hz, 1H), 7.47 (s, 1H), 7.30 (d,J=1.7 Hz, 1H), 7.27 (d, J=4.6 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H). LC/MS(10-99%) M/Z: M⁺1 obs=467.0; t_(R)=3.12 min.

2-(4-Fluoro-phenoxy)-N-[4-thiazol-2-ylsulfamoyl)-phenyl]-acetamide

4-Fluorophenol (0.050 g, 0.45 mmol) was dissolved in 1.0 mLdimethylacetamide containing K₂CO₃ (0.15 g, 2.5 equiv). tert-Butylchloroacetate (0.081 g, 85 μL, 1.2 equiv) was added neat and the mixturewas microwave irradiated at 150° C. for 30 min. After cooling, thecontents of the tube were filtered through Celite into a clean microwavetube, the bed was rinsed with 1.0 mL dimethylacetamide, 1.0 mL H₂O wasadded to the tube and this mixture was irradiated for 3 min at 190° C.Volatiles were evaporated. To the crude residue was addedcarbonyldiimidazole (0.68 mL of 1.0 M in DMA). The solution was placedon the shaker for 1.0 h at rt, after which N′-(2-thiazolyl)sulfanilamide(1.8 mL of 1.0 M in DMA) was added and shaking continued overnight atrt. Volatiles were again evaporated, and the product isolated by HPLCpurification.

2-(2-Ethyl-phenoxy)-N-[4-thiazol-2-ylsulfamoyl)-phenyl]-acetamide

2-Ethylphenol (0.061 g, 0.50 mmol) was dissolved in DMSO (0.5 mL) andpowdered K₂CO₃ (0.070 g, 0.50 mmol) was added followed by ethylbromoacetate (0.12 g, 86 μL neat, 1.2 equiv). The mixture was shaken atrt for 16 h. NaOH (1.0 mL of 2 N) was added and shaking continued for 4h. Aryloxybutanoic acid was precipitated by adding HCl (2.0 mL of 2 N)and collected by centrifugation and decantation of supernatant. A waterwash was similarly employed prior to evaporation of volatiles. The drycrude product was weighed and assumed to be pure as it was treated withcarbonyldiimidazole (1.0 equiv of 0.50 M in DMA) for 1 h at 45° C., thenN′-(2-thiazolyl)sulfanilamide (1.0 equiv of 1.0 M in DMA) was added andshaking continued overnight at rt. Volatiles were again evaporated, andthe product isolated by HPLC purification.

2-(4-Chloro-2-fluoro-phenoxy)-N-[4-thiazol-2-ylsulfamoyl)-phenyl]-acetamide

4-Chloro-2-fluorophenol (0.073 g, 0.50 mmol) was suspended in 0.62 mLH₂O and NaOH (0.10 mL, 10 N) was added. The mixture was shaken untilhomogenous, chloroacetic acid (0.50 mL of 1.0 M) was added and thesolution was heated to 110° C. in a test tube equipped with a rubber cappunctured by a syringe needle. Water was allowed to distill out. After4-5 h, the temperature was increased to about 120° C. and most of therest of the water was distilled off. When the volume reduction was about75%, the tube was cooled and 1.0 mL of 6 N HCl was added to precipitateproduct which was collected by centrifugation and decantation ofsupernatant. Water washes (2×2 mL) were similarly employed prior toevaporation of volatiles. The dry crude product was weighed and assumedto be pure as it was treated with carbonyldiimidazole (1.0 equiv of 0.50M in dimethylamine) for 1 h at 45° C., thenN′-(2-thiazolyl)sulfanilamide (1.0 equiv of 1.0 M in dimethylamine) wasadded and shaking continued overnight overnight at rt. Volatiles wereagain evaporated, and the product isolated by HPLC purification.

(8-Trifluoromethyl-quinolin-4-yloxy)-acetic acid

4-Hydroxy-8-trifluoromethylquinoline (0.50 g, 2.35 mmol) was dissolvedin DMSO (2 mL). Potassium carbonate was added (0.32 g, 2.35 mmol) andthe mixture was stirred vigorously for 2 h. Ethyl bromoacetate (0.32 mL,1.2 equiv) was added dropwise and heat was applied at 50° C. for 6 h. At50° C., 2N NaOH (2 mL) was added and stirring continued for 4 h. Themixture was cooled and quenched with water (4 mL). Glacial acetic acid(1.4 mL) was added to ˜pH 4 resulting in precipitation of product. Afterstirring the suspension for 6 h, the solid was collected by vacuumfiltration, rinsed with water, and dried in a vacuum dessicator overCaCl. The yield of white solid was 0.56 g (87%). ¹H-NMR (DMSO-d₆) 5.04(s, 2H), 7.11 (d, J=5.2 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 8.15 (d, J=8.0Hz, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.83 (d, J=5.2 Hz, 1H), 13.3 (br s,1H); LC/MS (10-99%) M/Z: M⁺1 obs=333.5; t_(R)=2.63 min.

N-[4-(Thiazol-2-ylsulfamoyl)-phenyl]-2-(8-trifluoromethyl-quinolin-4-yloxy)-acetamide

(8-Trifluoromethylquinolin-4-yloxy)-acetic acid (0.50 g, 1.84 mmol) wassuspended in 20 mL DCM with rapid stirring. At rt, oxalyl chloride (0.19mL, 1.2 equiv) was added dropwise and stirring continued for 4 h.Solvent and excess oxalyl chloride were removed in vacuo, the whiteresidue was re-suspended in DCM, and the mixture cooled to 0° C.N′-(2-thiazolyl)sulfanilamide (0.47 g, 1.0 equiv) was added followed bypyridine (0.30 mL, 2.0 equiv). The mixture was allowed to warm to rtovernight. The solid was collected and rinsed with fresh DCM. Furtherpurification was effected by suspending the solid in 20 mL methanol,stirring vigorously for 4 h, and filtration. After drying under vacuum,white solid 0.65 g (69%) was obtained. ¹H-NMR (DMSO-d₆) 5.11 (s, 2H),6.79 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 7.22 (d, J=4.8 Hz, 1H),7.71 (t, J=8.0 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H),8.85 (d, J=5.2 Hz, 1H),; ¹³C-NMR (DMSO-d₆) 68.0, 103.6, 108.8, 120.0,122.0, 124.8 (q, J=270 Hz), 125.1, 125.4, 126.4 (q, J=33 Hz), 127.7,127.8, 129.2, 137.7, 142.1, 145.6, 153.2, 161.2, 166.5, 169.4 LC/MS(10-99%) M/Z: M⁺1 obs=509.5; t_(R)=3.13 min.

6-Chloro-1,2,3,4-tetrahydroquinoline

Method A: To a solution of 6-chloroquinoline (2.0 g, 12.2 mmol) inanhydrous MeOH (500 mL) under nitrogen was added PtO₂ (0.2 g, 1.6 mmol).Hydrogen gas was then passed through the reaction mixture and themixture stirred for 45 min. The reaction mixture was filtered and thefiltrate evaporated. The product was taken up in DCM, filtered throughcelite and chromatographed (gradient of 0-10% EtOAc/Hex) to afford 0.9 g(41%) as clear colorless oil. HNMR (CDCl₃): δ 6.85-6.83 (m, 2H),6.42-6.39 (m, 1H), 5.82 (s, 1H), 3.17-3.13 (m, 2H), 2.63 (t, J=6.3 Hz,2H), 1.75 (q, J=5.9 Hz, 2H), LC/MS (10-99%) M/Z: M⁺1 obs=168.3;t_(R)=1.74 min.

Method B: A mixture of 6-chloroquinoline (0.82 g, 0.5 mmol), indiumpowder (0.53 g, 4.6 mmol), and saturated aq. NH₄Cl (789 μL) in absoluteEtOH (2.5 mL) was microwaved at 160° C. for 8 h. The mixture was thenfiltered and the filtrate concentrated to give a crude yield of 0.10 g.The product was taken up in DCM, filtered through celite andchromatographed (gradient of 0-10% EtOAc/Hex) to afford 0.01 g (12%) asclear colorless oil. LC/MS (10-99%) M/Z: M⁺1 obs=168.3; t_(R)=1.74 min.

1-Methyl-1,2,3,4-tetrahydro-isoquinoline

To a solution of 1-methylisoquinoline (133 μL, 1.0 mmol) in THF undernitrogen was added dropwise a solution of LiBEt₃H in THF (1.0M, 2.2 mL,2.2 mmol) to give a yellow solution. After stirring 1.5 h, MeOH (1.2 mL)was added dropwise to produce a clear colorless solution, which was thendiluted with 1M aq. HCl and ether. The aqueous layer was extracted threetimes with ether, then made basic (pH 14) by addition of 1M aq. NaOH.The aqueous layer was extracted five times with DCM, dried over MgSO₄,filtered and concentrated to give the desired product in 77% yield,which was used without further purification. LC/MS (10-99%) M/Z: M⁺1obs=148.3; t_(R)=0.62 min.

6-Methoxy-1,2,3,4-tetrahydro-quinoline

A mixture of 6-methoxyquinoline (69 μL, 0.5 mmol), ammonium formate(0.32 g, 5.0 mmol), and 10% Pd/C (0.05 g) in anhydrous MeOH (5 mL) wasmicrowaved for 900 s at 100° C. The mixture was filtered and 2M HCl inEt₂O (1.5 mL) was added. The product was redissolved in H₂O/DCM and theaqueous layer basified with 0.1M aq. NaOH (pH 8). After extracting threetimes with DCM, the organic layer was concentrated to give the productin 89% yield. The product was used without further purification. LC/MS(10-99%) M/Z: M⁺1 obs=164.0; t_(R)=0.40 min.

2-Chloro-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-acetamide

General procedure 1: N′-(2-thiazolyl)sulfanilamide (10.0 g, 39.2 mmol)was suspended in DCM containing pyridine (3.80 mL, 1.2 equiv) andchilled in an ice bath. Chloroacetyl chloride (5.3 g, 3.74 mL, 1.2equiv) was added dropwise with vigorous stirring. The mixture wasallowed to warm to rt overnight. The solid was filtered, rinsed withfresh DCM, and air dried to give 11.6 g (89%) white solid. ¹H-NMR(DMSO-d₆) 4.56 (s, 2H), 6.78 (d, J=4.8 Hz, 1H), 7.21 (d, J=4.8 Hz, 1H),7.70 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 10.61 (s, 1H); ¹³C-NMR(DMSO-d₆)44.2, 108.8, 119.7, 125.1, 127.7, 137.7, 142.3, 165.8, 169.4;LC/MS (10-99%) M/Z: M⁺1 obs=333.6; t_(R)=2.63 min.

2-(3,4-Dihydro-2H-quinolin-1-yl)-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-acetamide

General procedure 2: To the 2-chloroacetamide (2.00 g, 6.03 mmol) in DMF(15 mL) was added tetrahydroquinoline (2.27 mL, 18.09 mmol) and thereaction mixture was microwaved at 200° C. for 300 s. The reactionmixture was taken up in DCM, filtered through celite and chromatographed(gradient of 0-10% MeOH/DCM) to provide 1.53 g (59%) of a white solid.¹H-NMR (DMSO-d₆) 12.70 (s, 1H), 10.37 (s, 1H), 7.74 (s, 4H), 7.25 (d,J=5.6 Hz, 1H), 6.87-6.95 (m, 2H), 6.82 (d, J=4.6 Hz, 1H), 6.50 (t, J=7.3Hz, 1H), 6.42 (d, J=7.9 Hz, 1H), 3.41 (t, J=5.6 Hz, 2H), 2.73 (t, J=6.3Hz, 2H), 1.86-1.95 (m, 2H). LC/MS (10-99%) M/Z: M⁺1 obs=429.0;t_(R)=2.79 min.

2-(6-Chloro-3,4-dihydro-2H-quinoline-1-yl)-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-acetamide

Synthesized according to general procedure 2: 2-chloroacetamide (1.0 g,3.0 mmol), 6-chloro-tetrahydro-quinoline (0.85 g, 5.0 mmol) in DMF (15mL). Purified by column chromatography (5-10% MeOH/DCM), followed byHPLC purification (1-99% CH₃CN/H₂O). LC/MS (10-99%) M/Z: M⁺1 obs=463.3;t_(R)=2.93 min.

2-Indol-1-yl-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-acetamide

General procedure 3: A dry, 10 mL borosilicate glass reaction vessel wasput under an inert atmosphere of argon and loaded with sodium hydride(60% wt. dispersion in mineral oil, 5 equiv) to which dry DMF (1 mL) wasadded. The resulting suspension was cooled to 0° C. Subsequently, asolution of the indole in dry DMF (0.1M, 1 mL, 0.1 mmol) was added tothe vessel and the reaction mixture was stirred for 30 min. at 0° C.Next, a solution of the2-chloro-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-acetamide in dry DMF(0.1M, 1 mL, 1 equiv) was added. The reaction mixture was allowed towarm to room temperature and stirred for 72 h, after which the reactionwas quenched by the addition of water (5 mL). The work-up consisted ofwashing the aqueous phase with heptane (2×5 mL), addition of aqueous HCl(1M, 1 mL) and extraction with DCM (2×4 mL). Finally, removal of the DCMunder reduced pressure and stripping the resulting solid with CH₃CN (5times), afforded the final product. ¹H-NMR (DMSO-d₆): δ 10.73 (s, 1H),7.78-7.71 (m, 4H), 7.55 (d, J=7.7 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.38(d, J=3.0 Hz, 1H), 7.23 (d, J=4.7 Hz, 1H), 7.12 (t, J=7.4 Hz, 1H), 7.02(t, J=7.4 Hz, 1H), 6.80 (d, J=4.7 Hz, 1H), 6.46 (d, J=3.0 Hz, 1H), 5.09(s, 2H). LC/MS (10-99%) M/Z: M⁺1 obs=412.2; t_(R)=3.43 min.

2-(2-Methyl-2,3-dihydro-indol-1-yl)-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-acetamide

Synthesized according to general procedure 2: 2-chloroacetamide (0.5 g,1.5 mmol), 2-methylindoline (1.0 mL, 7.5 mmol) in DMF (5 mL). Purifiedby chromatography (gradient of 0-10% MeOH/DCM) to provide 640 mg (100%)of a white solid. ¹H-NMR (DMSO-d₆) 12.70 (bs, 1H), 10.26 (s, 1H),7.72-7.78 (m, 4H), 7.25 (d, J=4.6 Hz, 1H), 7.01 (d, J=7.2 Hz, 1H), 6.95(t, J=7.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 6.57 (dt, J=0.8 Hz, 1H), 6.39(d, J_(d)=0.8 Hz, J_(t)=8.0 Hz, 1H) (3.41 (t, J=5.6 Hz, 2H), 2.73 (t,J=6.3 Hz, 2H), 1.86-1.95 (m, 2H). LC/MS (10-99%) M/Z: M⁺1 obs=429.2;t_(R)=2.97 min.

2-Chloro-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-propionylamide

Synthesized according to general procedure 1:N′-(2-thiazolyl)sulfanilamide (1.00 g, 3.9 mmol), pyridine (0.6 mL),2-Chloropropionyl chloride (0.5 mL, 4.7 mmol, 1.2 equiv) in DCM (50 mL).Yield: 1.34 g (99%) of a crude white solid. ¹H-NMR (DMSO-d₆) 10.65 (s,1H), 7.73-7.79 (m, 4H), 7.25 (d, J=4.3, 1H), 6.83 (d, J=4.6, 1H), 4.69(q, J=3.3, 1H), 1.61 (d, J=6.6, 3H). LC/MS (10-99%) M/Z: M⁺1 obs=346.1;t_(R)=2.22 min.

2-(3,4-Dihydro-2H-quinolin-1-yl)-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-propionamide

Synthesized according to general procedure 2: 2-chloropropionylamide(173 mg, 0.5 mmol), tetrahydro-quinoline (0.19 mL, 1.5 mmol) in DMF (1mL), microwaved at 200° C. for 450 s. The reaction mixture was dilutedwith 50% MeOH/DMSO and purified by HPLC (gradient of 1-99% CH₃CN/water).¹H-NMR (DMSO-d₆) 10.29 (s, 1H), 7.72-7.79 (m, 4H), 7.25 (d, J=4.6, 1H),6.81-6.99 (m, 2H), 6.82 (d, J=4.6, 1H), 6.65 (d, 8.2, 1H), 6.54 (td,J_(d)=0.6, J_(t)=7.3, 1H), 4.58 (q, J=6.8, 1H), 3.47 (bs, 1H), 3.25 (t,J=5.5, 2H), 2.70 (t, J=6.2, 2H), 1.81-1.96 (m, 2H), 1.35 (d, J=6.9, 3H).LC/MS (10-99%) M/Z: M⁺1 obs=443.3; t_(R)=3.13 min.

2-(5-Chloro-indol-1-yl)-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-propionamide

Synthesized according to general procedure 3: 6-Chloroindole (0.1 g, 0.7mmol), NaH (60% in oil, 0.14 g, 3.6 mmol), 2-chloropropionylamide (250mg, 0.7 mmol). The product was isolated by HPLC (gradient of 10-99%CH₃CN/water). ¹H-NMR (DMSO-d₆) 10.71 (bs, 1H), 7.71-7.83 (m, 4H), 7.65(d, J=1.6, 1H), 7.58-7.59 (m, 1H), 7.56 (s, 1H), 7.24 (d, 4.6, 1H), 7.05(dd, J=1.8, 8.4, 1H), 6.81 (d, J=4.6, 1H), 6.53 (dd, J=0.5, 2.8, 1H),5.37 (q, J=7.0, 1H), 1.75 (d, J=6.9, 3H) LC/MS (10-99%) M/Z: M⁺1obs=461.3; t_(R)=2.90 min.

2-Chloro-2-phenyl-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-acetamide

Synthesized according to general procedure 1:N′-(2-thiazolyl)sulfanilamide (5.60 g, 22 mmol), pyridine (3.6 mL, 44mmol), 2-chloro-2-phenyl acetylchloride (3.8 mL, 26.4 mmol, 1.2 equiv)in DCM (400 mL). Yield: 6.73 g (75%) of a white solid. ¹H-NMR (DMSO-d₆)δ 10.85 (s, 1H), 7.78-7.72 (m, 4H), 7.60-7.57 (m, 2H), 7.45-7.37 (m,3H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 5.77 (s, 1H). LC/MS(10-99%) M/Z: M⁺1 obs=408.1; t_(R)=2.61 min.

2-(3,4-Dihydro-2H-quinolin-1-yl)-2-phenyl-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-acetamide

Synthesized according to general procedure 2: 2-chloro-2-phenylacetamide (61 mg, 0.15 mmol), tetrahydroquinoline (94 μL, 0.75 mmol) inDMF (0.75 mL), microwaved at 200° C. for 300 s. The reaction mixture wasdiluted with 50% MeOH/DMSO (0.75 mL) and purified by HPLC (gradient of1-99% CH₃CN/water). ¹H-NMR (DMSO-d₆) δ 10.74 (s, 1H), 7.79-7.74 (m, 4H),7.44-7.31 (m, 5H), 7.25 (d, J=4.6 Hz, 1H), 6.99 (d, J=7.4 Hz, 1H), 6.95(d, J=7.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H),6.58-6.55 (m, 1H), 5.75 (s, 1H), 3.40-3.36 (m, 1H), 2.94-2.89 (m, 1H),2.79-2.61 (m, 2H), 1.83-1.67 (m, 2H). LC/MS (10-99%) M/Z: M⁺1 obs=505.3;t_(R)=3.20 min.

3-Chloro-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-propionamide

Synthesized according to general procedure 1:N′-(2-thiazolyl)sulfanilamide (8.37 g, 32.8 mmol), pyridine (5.3 mL,65.6 mmol), 2-chloro-propionylchloride (3.8 mL, 39.4 mmol, 1.2 equiv) inDCM (400 mL). Yield: 2.70 g (24%) of a white solid. ¹H-NMR (DMSO-d₆) δ10.41 (s, 1H), 7.77-7.72 (m, 4H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6Hz, 1H), 3.88 (t, J=6.2 Hz, 2H), 2.86 (t, J=6.2 Hz, 2H). LC/MS (10-99%)M/Z: M⁺1 obs=346.1; t_(R)=1.94 min.

2-(3,4-Dihydro-2H-quinolin-1-yl)-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-propionamide

Synthesized according to general procedure 2: 3-chloro-propionamide (173mg, 0.5 mmol), tetrahydroquinoline (188 μL, 1.5 mmol) in DMF (5.0 mL),microwaved at 200° C. for 300 s. The reaction mixture was diluted with50% MeOH/DMSO (5.0 mL) and purified by HPLC (gradient of 1-99%CH₃CN/water). ¹H-NMR (DMSO-d₆) δ 10.32 (s, 1H), 7.75-7.70 (m, 4H), 7.25(d, J=4.6 Hz, 1H), 7.00-6.96 (m, 1H), 6.87 (dd, J=7.3, 1.4 Hz, 1H), 6.82(d, J=4.6 Hz, 1H), 6.64 (d, J=7.9 Hz, 1H), 6.48 (dt, J=10.0, 3.6 Hz,1H), 3.59 (t, J=7.0 Hz, 2H), 3.25 (t, J=5.6 Hz, 2H), 2.69-2.53 (m, 4H),1.86-1.80 (m, 2H). LC/MS (10-99%) M/Z: M⁺1 obs=443.3; t_(R)=2.42 min.

3-(6-Chloro-indol-1-yl)-N-[4-(Thiazol-2-ylsulfamoyl)-phenyl]-propionamide

Synthesized according to general procedure 3: 6-Chloroindole (109 mg,0.72 mmol), NaH (60% in oil, 144 mg, 3.60 mmol), 3-chloropropionamide(250 mg, 0.72 mmol). The product was isolated by HPLC (gradient of10-99% CH₃CN/water). ¹H-NMR (DMSO-d₆) δ 10.25 (s, 1H), 7.73-7.64 (m,4H), 7.53 (d, J=8.3 Hz, 1H), 7.37 (d, J=3.1 Hz, 1H), 7.21 (d, J=4.5 Hz,1H), 7.02 (dd, J=8.4, 1.9 Hz, 1H), 6.43 (d, J=0.8 Hz, 1H), 4.50 (t,J=6.6 Hz, 2H), 2.84 (t, J=6.7 Hz, 2H). LC/MS (10-99%) M/Z: M⁺1obs=461.1; t_(R)=2.84 min.

[4-(Thiazol-2-ylsulfamoyl)-phenyl]-carbamic acid8-trifluoromethyl-quinolin-4-yl ester

To a solution of 8-trifluoromethyl-quinolin-4-ol (107 mg, 0.50 mmol) inTHF (5 mL) was added 4-isocyanatobenzene-sulfonyl chloride (109 mg, 0.50mmol) at RT. The resulting mixture was stirred at ambient temperaturefor 1 h. Then, a solution of 2-aminothiazole (50 mg, 0.50 mmol) inpyridine (5 mL) was added and stirring was continued for 65 h. Thesolvents were evaporated under a stream of nitrogen, the residue wasdissolved in DMSO (2 mL) and purified by preparative LC/MS (gradient of5-95% CH₃CN/water). ¹H-NMR (DMSO-d₆) δ 9.63 (s, 1H), 9.10 (s, 1H),8.28-8.22 (m, 2H), 7.97-7.95 (m, 2H), 7.81-7.77 (m, 3H), 7.52-7.51 (m,1H), 7.41-7.40 (m, 2H), 7.15-7.14 (m, 1H). LC/MS (5-95%) M/Z: M⁺1obs=495.4; t_(R)=10.45.

4-(3-Quinolin-8-yl-ureido)-N-thiazol-2-yl-benzenesulfonamide

Method A: To a solution of sulfathiazole (102 mg, 0.40 mmol) andN,N-diisopropylethylamine (0.17 mL, 0.95 mmol) in acetonitrile (10 mL)was added a 20% phosgene solution in toluene (20% w/w in toluene, 1 mL).The reaction mixture was stirred under reflux for 2 h. The excess ofphosgene and solvent were evaporated in vacuo and coevaporated withacetonitrile (5 mL). Then, the crude product was suspended inacetonitrile (5 mL), and a solution of 8-aminoquinoline (58 mg, 0.40mmol) in acetonitrile (1 mL) was added. The resulting mixture wasstirred at reflux for 16 h. After cooling to RT, the reaction mixturewas filtered and washed with acetonitrile (5 mL), water (2×5 mL) anddiisopropylether (5 mL). The urea precipitated during the washing stepsand was collected by filtration. The solid was washed with water (5 mL)and diisopropylether (5 mL) and dried in vacuo to give the product (18mg, 11%). ¹H-NMR (DMSO-d₆) δ 10.24 (s, 1H), 9.80 (s, 1H), 8.94-8.93 (m,1H), 8.57-8.55 (m, 1H), 8.42-8.40 (m, 1H), 7.76-7.57 (m, 7H), 7.25-7.24(m, 1H), 6.82-6.81 (m, 1H). LC/MS (5-95%) M/Z: M⁺1 obs=424.6;t_(R)=8.44.

Method B: To a solution of 8-aminoquinoline (72 mg, 0.50 mmol) inacetonitrile (5 mL) was added diphosgene (66 μL, 0.55 mmol). The mixturewas stirred under reflux for 2 h. Then, sulfathiazole (125 mg, 0.49mmol) and triethylamine (167 μL, 1.12 mmol) were added. The mixture wasstirred under reflux for another 2 h and then allowed to reach ambienttemperature overnight. Water (5 mL) was added, and the solid wasfiltered off, washed with water and cold acetonitrile and dried invacuo.

(4-Nitrophenyl)-thiazol-2-yl-amine

To a suspension of 1-(4-nitrophenyl)-2-thiourea (5.00 g, 25.4 mmol) inacetic acid (40 mL) was added bromoacetaldehyde diethyl acetal (3.94 mL,25.4 mmol) at RT. The resulting mixture was heated to 100° C. for 2 h.After cooling to RT, the solvent was removed in vacuo. The residue wasdiluted with 1M NaOH (100 mL) and EtOAc (100 mL). The phases wereseparated, and the aqueous phase was extracted with EtOAc (2×100 mL).The combined organic extracts were dried over MgSO₄ and concentrated.Purification by column chromatography (20-80% EtOAc in hexanes) affordedthe product as a yellow solid (2.75 g, 49%). ¹H-NMR (400 MHz, DMSO-d₆) δ11.02 (s, 8.231H), 8.23 (d, J=9.3 Hz, 2H), 7.85 (d, J=9.3 Hz, 2H), 7.41(d, J=3.6 Hz, 1H), 7.15 (d, J=3.6 Hz, 1H). LC/MS (10-99%) M/Z: M⁺1obs=222.1; t_(R)=2.50 min.

N-Thiazol-2-yl-benzene-1,4-diamine

A mixture of 4-Nitrophenyl)-thiazol-2-yl-amine (917 mg, 4.15 mmol) andtin(II) chloride (2.36, 12.5 mmol) in EtOH (40 mL) and 1M HCl (40 mL)was heated to 80° C. for 6 h. After cooling to RT, water (100 mL) andEtOAc (100 mL) were added and the phases were separated. The aqueousphase was neutralized by addition of 1M NaHCO₃ and extracted with EtOAc(4×150 mL). The combined organic extracts were dried over MgSO₄ andconcentrated. The residue was filtered through a silica pad(hexanes:EtOAc, 1:1), and the filtrate was concentrated to give theproduct as a yellow-white solid (340 mg, 39%). ¹H-NMR (400 MHz, DMSO-d₆)δ 9.56 (s, 1H), 7.21 (d, J=6.6 Hz, 2H), 7.12 (d, J=3.6 Hz, 1H), 6.70 (d,J=3.7 Hz, 1H), 6.53 (d, J=6.6 Hz, 2H), 4.81 (s, 2H). LC/MS (10-99%) M/Z:M⁺1 obs=192.3; t_(R)=0.39 min.

{4-[(Thiazole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

To a solution of 2-TMS-thiazole (2.25 mL, 14.1 mmol) in DCM (5 mL) at 0°C. was slowly added a solution of phosgene in toluene (20%, 7.45 mL,14.1 mmol) over 15 Min. After stirring for 2 h at RT, the resultingsolution was slowly added via syringe to a solution ofN-BOC-1,4-phenylenediamine (4.42 g, 21.2 mmol) and pyridine (2.3 mL,28.2 mmol) in DCM (100 mL) at 0° C. After stirring for 20 h at RT, thereaction mixture was quenched by addition of sat. NaHCO₃ (100 mL), EtOAc(150 mL) was added, and the phases were separated. The aqueous phase wasextracted with EtOAc (2×75 mL), and the combined organic extracts weredried over MgSO₄ and concentrated in vacuo. Purification by columnchromatography (10-50% EtOAc in hexanes) afforded the product as anorange solid (452 mg, 10%). ¹H-NMR (400 MHz, DMSO-d₆) δ 10.66 (s, 1H),9.34 (s, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.09 (d, J=3.1 Hz, 1H), 7.72 (d,J=7.0 Hz, 2H), 7.42 (d, J=8.9 Hz, 2H), 1.48 (s, 9H). LC/MS (10-99%) M/Z:M⁺1 obs=320.3; t_(R)=2.90 min.

Thiazole-2-carboxylic acid (4-amino-phenyl)-amide

To a solution of the N-BOC-protected amine (452 mg, 1.42 mmol) in DCM(2.5 mL) was added TFA (2.5 mL). After stirring for 1 h at RT, thereaction mixture was poured into sat. NaHCO₃ (50 mL) and extracted withEtOAc (2×50 mL). The combined organic extracts were dried over MgSO₄,concentrated in vacuo and used without further purification in the nextreaction. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.26 (s, 1H), 7.99 (d, J=3.1 Hz,1H), 7.97 (d, J=3.1 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H), 6.45 (d, J=8.8 Hz,2H), 4.92 (s, 2H). LC/MS (10-99%) M/Z: M⁺1 obs=220.3; t_(R)=0.57 min.

Thiazole-2-carboxylic acid 4-tert-butoxycarbonylamino-phenyl ester

To a solution of 2-TMS-thiazole (2.25 mL, 14.1 mmol) in DCM (5 mL) at 0°C. was slowly added a solution of phosgene in toluene (20%, 7.45 mL,14.1 mmol) over 15 Min. After stirring for 2 h at RT, the resultingsolution was slowly added via syringe to a solution ofN-BOC-4-hydroxyaniline (4.39 g, 21.2 mmol) and pyridine (2.3 mL, 28.2mmol) in DCM (100 mL) at 0° C. After stirring for 20 h at RT, thereaction mixture was quenched by addition of sat. NaHCO₃ (100 mL), EtOAc(150 mL) was added, and the phases were separated. The aqueous phase wasextracted with EtOAc (2×75 mL), and the combined organic extracts weredried over MgSO₄ and concentrated in vacuo. Purification by columnchromatography (10-50% EtOAc in hexanes) afforded the product as a greensolid (518 mg, 12%). ¹H-NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H) 8.29 (d,J=3.0 Hz, 1H), 8.22 (d, J=3.0 Hz, 1H), 7.53 (d, J=8.9 Hz, 2H), 7.23 (d,J=6.9 Hz, 2H), 1.48 (s, 9H) LC/MS (10-99%) M/Z: M⁺1 obs=321.1;t_(R)=2.94 min.

Thiazole-2-carboxylic 4-amino-phenyl ester

To a solution of the N-BOC-protected amine (515 mg, 1.61 mmol) in DCM(2.5 mL) was added TFA (2.5 mL). After stirring for 1 h at RT, thereaction mixture was poured into sat. NaHCO₃ (50 mL) and extracted withEtOAc (2×50 mL). The combined organic extracts were dried over MgSO₄,concentrated in vacuo and used without further purification in the nextreaction. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=3.0 Hz, 1H), 8.19 (d,J=3.0 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 6.59 (d, J=8.8 Hz, 2H), 5.17 (s,2H). LC/MS (10-99%) M/Z: M⁺1 obs=221.1; t_(R)=0.59 min.

3-(3,4-Dihydro-2H-quinolin-1-yl)-propionic acid

A solution of ethyl bromoacetate (0.75 g, 4.5 mmol) and1,2,3,4-tetrahydroquinoline (0.57 mL, 4.5 mmol) in DMF (10 mL) wasmicrowaved at 200° C. for 300 s. The solvent was removed in vacuo, andthe residue was redissolved in MeOH (12.5 mL). 1M NaOH (12.5 mL) wasadded, and the reaction mixture was heated to 80° C. for 2.5 h. Aftercooling to RT, EtOAc (30 mL) and water (30 mL) were added, the phaseswere separated, the aqueous layer was acidified to pH 2-3 by addition of6M HCl and extracted with EtOAc (3×30 mL). The combined organic extractswere dried over MgSO₄ and concentrated in vacuo to give the product (640mg, 75%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 6.94-6.88 (m,2H), 1H), 6.38 (d, J=8.2 Hz, 1H), 3.98 (s, 2H), 3.32 (t, J=5.6 Hz, 2H),2.69 (t, J=6.3 Hz, 2H), 1.92-1.84 (m, 2H). LC/MS (10-99%) M/Z: M⁺1obs=192.3; t_(R)=2.39 min.

General Procedure 4 for Amide Couplings:

A mixture of the corresponding acid (0.2 mmol), amine (0.2 mmol),triethylamine (28 μL, 0.2 mmol) and HATU (76 mg, 0.2 mmol) in pyridine(0.5 mL) was microwaved at 200° C. for 420 s. The reaction mixture wasdiluted with 50% DMSO/MeOH (0.5 mL), filtered and purified by HPLC(gradient of 10-99% CH₃CN/water).

4-(2,4-Dichloro-phenoxy)-N-[4-(thiazol-2-ylamino)-phenyl]-butyramide

Synthesized according to general procedure 4. ¹H-NMR (400 MHz, DMSO-d₆)δ 10.09 (s, 1H), 9.86 (s, 1H), 7.58-7.50 (m, 5H), 7.37 (dd, J=8.9, 2.6Hz, 1H), 7.23-7.19 (m, 2H), 6.86 (d, J=3.7 Hz, 1H), 4.12 (t, J=6.3 Hz,2H), 2.56-2.45 (m, 2H), 2.09-2.02 (m, 2H). LC/MS (10-99%) M/Z: M⁺1obs=422.1; t_(R)=2.67 min.

2-(3,4-Dihydro-2H-quinolin-1-yl)-N-[4-thiazol-2-ylamino)-phenyl]-acetamide

Synthesized according to general procedure 4. ¹H-NMR (400 MHz, DMSO-d₆)δ 10.15 (s, 1H), 9.88 (s, 1H), 7.56-7.51 (m, 4H) 7.23 (d, J=3.7 Hz, 1H),6.95-6.87 (m, 3H), 6.50 (td, J=7.3, 0.9 Hz, 1H), 6.44 (d, J=8.1 Hz, 4.02(s, 2H), 3.42 (t, J=5.6 Hz, 2H), 2.72 (t, J=6.3 Hz, 2H), 1.96-1.90 (m,2H). LC/MS (10-99%) M/Z: M⁺1 obs=365.1; t_(R)=2.41 min.

N-[4-(Thiazol-2-ylamino)-phenyl]-2-(8-trifluoromethyl-quinolin-4-yloxy)-acetamide

Synthesized according to general procedure 4. ¹H-NMR (400 MHz, DMSO-d₆)δ 10.23 (s, 1H), 10.19 (s, 1H), 8.90 (d, J=5.3 Hz, 1H), 8.63 (d, J=7.6Hz, 1H), 8.22 (d, J=6.8 Hz, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.61-7.52 (m,4H), 7.24 (d, J=3.7 Hz, 1H), 7.17 (d, J=5.3 Hz, 1H), 6.89 (d, J=3.7 Hz,1H), 5.08 (s, 2H). LC/MS (10-99%) M/Z: M⁺1 obs=445.3; t_(R)=2.29 min.

Thiazole-2-carboxylic acid{4-[4-(2,4-dichloro-phenoxy)-butyrylamino]phenyl}-amide

Synthesized according to general procedure 4. ¹H-NMR (400 MHz, DMSO-d₆)δ H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 9.98 (s, 1H), 8.13 (d, J=3.1Hz, 1H), 8.10 (d, J=3.1 Hz, 1H), 7.79-7.75 (m, 2H), 7.59-7.56 (m, 3H),7.37 (dd, J=8.9, 2.6 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 4.13 (t, J=6.3 Hz,2H), 3.37-3.31 (m, 2H), 2.09-2.03 (m, 2H). LC/MS (10-99%) M/Z: M⁺1obs=450.3; t_(R)=3.34 min.

Thiazole-2-carboxylic acid[4-(2,3,4-dihydro-2H-quinolin-1-yl-acetylamino)-phenyl]-amide

Synthesized according to general procedure 4. ¹H-NMR (400 MHz, DMSO-d₆)δ H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 10.00 (s, 1H), 8.13 (d,J=3.1 Hz, 1H), 8.10 (d, J=3.1 Hz, 1H), 7.78 (d, J=9.0 Hz, 2H), 7.58 (d,J=9.0 Hz, 2H), 6.96-6.89 (m, 2H), 6.52-6.44 (m, 2H), 4.05 (s, 2H), 3.42(t, J=5.6 Hz, 2H), 2.73 (t, J=6.3 Hz, 2H), 1.96-1.90 (m, 2H). LC/MS(10-99%) M/Z: M⁺1 obs=393.1; t_(R)=3.07 min.

Thiazole-2-carboxylic acid{4-[2-(8-trifluoromethyl-quinolin-4-yloxy)-acetylamino]-phenyl}-amide

Synthesized according to general procedure 4. ¹H-NMR (400 MHz, DMSO-d₆)δ 10.78 (s, 1H), 10.34 (s, 1H), 8.90 (d, J=5.3 Hz, 8.63 (d, J=8.1 Hz,1H), 8.22 (d, J=7.0 Hz, 1H), 8.14 (d, J=3.1 Hz, 1H), 8.11 (d, J=3.1 Hz,1H), 7.84-7.82 (m, 2H), 7.76 (t, J=7.9 Hz, 1H), 7.63-7.61 (m, 2H), 7.18(d, J=5.3 Hz, 1H), 5.11 (s, 2H). LC/MS (10-99%) M/Z: M⁺1 obs=473.1;t_(R)=2.82 min.

Thiazole-2-carboxylic acid4-[4-(2,4-dichlorophenoxy)-butyrylamino]-phenyl ester

Synthesized according to general procedure 4. ¹H-NMR (400 MHz, DMSO-d₆)δ H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.30 (d, J=3.0 Hz, 1H), 8.24(d, J=3.0 Hz, 1H), 7.71-7.67 (m, 2H), 7.58 (d, J=2.6 Hz, 1H), 7.38 (dd,J=8.9, 2.6 Hz, 1H), 7.30-7.26 (m, 2H), 7.21 (d, J=8.9 Hz, 1H), 4.14 (t,J=6.3 Hz, 2H), 2.55 (t, 2H), 2.34-2.30 (m, 2H). LC/MS (10-99%) M/Z: M⁺1obs=451.0; t_(R)=3.58 min.

Thiazole-2-carboxylic acid4-(2,3,4-dihydro-2H-quinolin-1-yl-acetylamino)-phenyl ester

Synthesized according to general procedure 4. ¹H-NMR (400 MHz, DMSO-d₆)δ H NMR (400 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.30 (d, J=3.0 Hz, 1H), 8.23(d, J=3.0 Hz, 1H), 7.72-7.68 (m, 2H), 7.31-7.27 (m, 2H), 6.96-6.90 (m,2H), 6.51 (dt, J=9.7, 3.9 Hz, 1H), 6.45 (d, J=8.1 Hz, 1H), 4.08 (s, 2H),3.43 (t, J=5.6 Hz, 2H), 2.73 (t, J=6.3 Hz, 2H), 1.96-1.90 (m, 2H). LC/MS(10-99%) M/Z: M⁺1 obs=394.2; t_(R)=3.30 min.

Thiazole-2-carboxylic acid4-[2-(8-trifluoromethyl-quinolin-4-yloxy)-acetylamino]-phenyl ester

Synthesized according to general procedure 4. ¹H-NMR (400 MHz, DMSO-d₆)δ H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 8.90 (d, J=5.3 Hz, 1H), 8.63(d, J=7.7 Hz, 1H), 8.31 (d, J=3.0 Hz, 1H), 8.24 (d, J=3.0 Hz, 1H), 8.22(d, J=7.0 Hz, 1H), 7.78-7.71 (m, 3H), 7.36-7.32 (m, 2H), 7.19 (d, J=5.3Hz, 1H), 5.14 (s, 2H). LC/MS (10-99%) M/Z: M⁺1 obs=474.0; t_(R)=3.06min.

The analytical data for selected compounds recited in FIG. 1 are shownbelow in Table 2.

TABLE 2 LC/MS RT Cmpd # M⁺ (min) 4 390.20 2.51 36 440.00 4.30 38 441.002.43 43 388.00 2.56 63 447.20 3.06 74 408.00 3.95 91 440.30 2.96 110454.10 2.97 124 374.00 2.59 127 428.00 2.87 142 495.00 3.23 143 486.202.96 144 453.00 3.01 147 445.20 3.23 155 467.20 3.11 157 403.00 3.16 161400.00 2.63 162 411.00 2.18 163 411.00 1.99 164 401.00 2.18 165 425.002.13 166 411.00 2.86 167 414.00 2.81 168 440.00 2.90 170 442.20 1.85 171427.10 3.09 172 402.30 2.53 173 447.30 3.03 174 427.30 2.61 175 404.002.55 186 408.00 2.62 193 475.00 3.11 225 426.00 2.86 232 480.00 3.16 233501.20 3.29 234 498.20 3.25 235 484.00 3.49 236 498.20 3.51 237 511.203.26 238 509.20 3.26 239 511.20 3.31 240 481.00 3.24 241 511.20 3.34 242432.20 2.97 243 453.00 3.12 244 450.00 3.07 245 436.20 3.32 246 463.203.09 247 461.20 3.05 248 463.20 3.13 249 433.20 3.03 250 428.20 2.89 251461.20 3.07 252 479.00 3.25 253 479.00 3.12 254 466.00 3.10 255 515.003.84 256 463.20 3.15 257 449.20 3.10 258 454.00 3.04 259 411.00 3.11 260446.20 3.02 261 469.00 3.20 262 452.00 3.41 263 397.00 3.04 264 450.003.37 265 463.20 3.19 266 469.00 3.07 267 473.00 3.19 268 483.00 3.17 269405.20 2.70 270 415.00 2.59 271 420.80 2.72 272 401.00 2.56 273 406.002.55 274 411.20 2.81 275 417.20 2.90 276 397.20 2.76 277 427.20 2.96 278402.20 2.75 279 458.20 2.98 280 474.20 1.98 281 389.00 3.05 282 431.203.15 283 465.80 3.14 284 481.00 3.21 285 487.00 3.27 286 484.20 3.21 287470.20 3.46 288 484.20 3.47 289 497.20 3.21 290 495.20 3.20 291 497.203.24 292 466.80 3.16 293 497.20 3.28 294 472.20 3.09 295 432.20 2.79 296447.20 2.90 297 453.20 2.95 298 463.20 2.92 299 461.40 2.89 300 463.203.00 301 433.40 2.85 302 438.20 2.79 303 389.20 2.35 304 374.60 2.92 305417.00 3.06 306 470.20 3.07 307 470.00 3.34 308 485.20 3.08 309 483.003.15 310 452.00 2.95 311 536.20 3.48 312 592.20 3.55 313 596.20 3.62 314514.20 3.27 315 526.20 3.31 316 542.40 3.53 317 562.40 3.53 318 500.003.37 319 527.20 3.37 320 487.00 3.09 321 455.80 3.31 322 481.00 3.05 323404.20 2.49 324 397.20 2.37 325 471.20 3.66 326 457.40 3.60 327 471.203.74 328 485.40 3.78 329 471.20 3.81 330 485.40 3.87 331 473.20 3.42 332417.20 3.22 333 431.40 3.36 334 443.40 3.42 335 459.40 3.72 336 493.203.67 337 489.00 3.69 338 432.20 3.00 339 417.20 2.81 340 435.20 2.43 341441.20 2.57 342 426.00 2.39 343 409.20 2.69 344 415.00 2.82 345 400.002.65 346 459.20 3.10 347 465.00 3.18 348 461.20 3.18 349 466.80 3.26 350452.00 3.07 351 421.00 2.55 352 427.00 2.69 353 411.60 2.51 354 385.002.62 355 391.20 2.69 356 376.00 2.55 357 410.20 2.62 358 476.20 3.22 359482.20 3.26 360 467.00 3.12 361 410.20 2.78 362 467.90 4.06 363 474.864.05 364 459.86 3.87 365 437.89 3.79 366 467.90 4.10 367 474.85 4.23 368459.84 3.95 369 475.99 4.30 370 465.92 4.13 371 460.95 3.95 372 467.964.00 373 451.92 3.83 374 466.90 4.29 375 451.95 4.10 376 424.90 3.63 377438.90 3.93 378 433.20 2.80 379 433.20 2.80 380 424.00 2.85 381 443.202.94 382 449.00 3.10 383 434.00 2.96 384 487.20 2.57 385 472.20 2.41 386439.20 2.71 387 445.40 2.84 388 430.10 2.79 389 425.20 2.89 390 431.002.98 391 416.20 2.82 392 429.20 3.27 393 420.20 3.15 394 537.20 3.58 395528.20 3.50 396 525.40 3.45 397 519.00 3.40 398 510.20 3.29 399 500.003.19 400 514.00 3.04 401 455.40 3.74 402 521.40 3.79 403 459.00 1.70 404408.20 2.63 405 414.20 2.74 406 399.00 2.60 407 422.20 2.89 408 428.202.96 409 413.00 2.84 410 429.50 2.68 411 399.10 2.51 412 417.10 2.78 413483.30 3.08 414 413.30 2.83 415 411.30 2.83 416 427.00 2.90 417 459.002.32 418 509.00 3.32 419 475.00 3.10 420 500.00 3.23 421 500.00 3.21 422470.00 3.19 423 447.00 3.05 424 433.00 2.86 425 399.00 2.58 426 451.002.81 428 502.00 4.42 429 432.00 4.29 430 486.00 4.41 431 486.00 4.36 432436.00 4.09 439 462.00 4.54 440 434.00 4.09 441 424.00 4.19 442 415.003.82 443 432.00 3.72 444 454.00 4.19 448 404.00 4.15 471 100.00 3.30 472497.20 3.60 473 443.40 3.15 474 100.00 3.37 475 158.00 2.98 476 436.004.12 477 432.00 4.49 478 418.00 4.27 479 454.00 4.12 480 420.00 3.97 481442.00 4.20 482 537.00 3.40 484 456.00 4.07 485 470.00 4.30 486 466.004.02 487 434.00 3.92 488 484.00 4.44 489 447.00 3.47 490 444.00 3.69 491472.00 4.52 492 520.00 4.47 493 458.00 3.70 494 509.00 3.60 495 445.003.84 496 461.00 3.82 497 464.00 4.15 498 461.00 4.00 499 432.00 3.95 500504.00 4.41 501 504.00 4.44 502 472.00 4.44 503 520.00 4.38 504 473.003.45 505 471.00 3.62 506 416.00 3.45 507 462.00 3.38 508 454.00 3.80 509459.00 3.99 510 451.00 3.26 511 475.00 4.02 512 443.00 5.27 513 492.005.43 514 435.00 3.63 515 477.00 3.74 516 487.00 4.39 517 521.00 4.39 518500.00 4.19 519 482.00 3.77 520 470.00 3.87 521 488.00 4.30 522 470.003.94 523 451.00 4.01 524 453.00 4.02 525 480.00 4.07 526 470.00 3.89 527463.00 3.95 528 521.00 4.39 529 482.00 4.04 530 502.00 4.46 531 454.004.15 532 447.00 3.74 533 433.00 3.40 534 460.00 3.32 535 474.00 3.50 536434.00 3.34 537 476.00 4.12 538 455.00 3.41 539 441.00 5.36 540 442.003.12 541 510.00 4.44 542 450.00 5.70 543 443.00 4.72 544 451.00 4.31 545441.00 5.10 546 444.00 3.81 547 444.00 4.72 548 426.00 3.57 549 459.003.95 550 442.30 0.57 551 381.10 2.36 552 456.30 2.98 553 492.30 3.17 554424.10 2.46 555 466.10 3.07 556 400.30 2.70 557 479.10 2.23 558 506.103.12 559 436.00 2.55 560 418.00 2.68 561 450.00 2.79 562 429.00 2.71 563415.00 2.59 564 460.00 3.63 565 462.00 5.07 566 436.00 3.69 567 448.003.45 568 523.00 5.15 569 448.00 3.57 570 504.00 4.00 571 500.00 4.14 572448.00 3.52 573 477.00 3.67 574 465.00 4.97 575 467.00 2.58 576 444.004.38 577 490.00 4.79 578 399.10 2.29 579 413.30 2.43 580 400.30 1.73 581428.30 1.88 582 427.30 2.65 583 427.30 2.51 584 477.10 2.93 585 431.302.55 586 411.10 2.75 587 414.30 2.86 588 442.00 4.89 589 470.00 3.42 590260.10 3.20 591 246.30 3.10 592 430.30 2.68 593 234.10 2.71 594 416.302.60 595 425.10 1.79 596 425.10 1.78 597 457.30 2.18 598 444.00 2.84 599464.00 3.07 600 484.00 3.10 601 494.00 3.04 602 500.00 3.00 603 500.003.05 604 530.00 3.18 605 470.00 4.51 606 473.00 4.66 607 457.00 2.78 608418.00 3.09 609 397.00 2.01 610 429.00 2.14 611 486.00 3.29 612 500.003.37 613 474.00 3.01 614 446.00 3.68 615 441.00 1.87 616 442.00 2.29 617443.00 2.67 618 442.00 2.21 619 430.00 3.04 620 442.00 2.77 621 430.002.80 622 430.00 3.06 623 414.00 1.93 624 439.00 2.19 625 443.00 2.31 626425.00 2.11 627 434.00 2.85 628 464.00 2.93 629 429.00 2.78 630 433.002.71 631 449.00 2.87 632 497.00 3.03 633 485.00 3.28 634 442.00 2.29 635442.00 2.25 636 473.00 2.62 637 475.00 2.93 638 442.00 2.91 639 442.003.05 640 475.00 2.12 641 459.00 2.02 642 459.00 1.84 643 430.00 2.14 644509.00 2.43 645 413.00 2.55 646 399.00 2.36 647 528.00 2.30 648 563.304.71 649 563.30 4.71 650 487.30 3.13 651 517.10 3.28 652 517.10 3.32 653528.90 3.45 654 308.10 3.25 655 497.10 3.12 656 489.00 1.98 657 445.002.64 658 429.00 1.92 659 487.00 3.41 660 459.00 2.83 682 480.00 3.19 683438.00 684 426.00 685 426.00 686 440.00 687 464.00 688 440.00 689 444.00690 456.00 691 460.00 693 440.00 694 443.00 2.99 695 443.00 2.83 696463.00 3.08 697 457.00 2.44 698 471.00 2.57 699 443.00 2.48 700 471.002.49 701 576.00 3.54 702 628.00 3.67 703 610.00 3.69 704 611.00 3.68 705594.00 3.52 706 555.00 3.64 707 515.00 3.36 708 447.00 2.82 709 443.002.00 710 457.00 3.10 711 457.00 3.13 712 443.00 3.13 713 443.00 3.16 714523.00 2.64 715 463.00 3.04 716 443.00 1.92 717 367.00 0.68 718 383.000.62 719 403.00 1.68 720 381.00 1.17 721 461.00 2.90 722 443.00 2.42 723461.00 2.84 724 461.00 2.84 725 429.00 2.76 726 443.00 2.67 727 505.003.20 728 395.00 1.55 729 395.00 1.68 730 409.00 1.82 731 417.00 1.65 732399.00 1.40 733 417.00 1.56 734 445.00 2.70 735 445.00 2.70 736 409.001.40 737 424.00 0.86 738 424.00 0.67 739 395.00 1.49 740 447.00 2.41 741443.00 2.58 742 495.00 3.00 743 445.00 2.70 744 461.00 2.80 745 452.002.50 746 449.00 2.70 747 444.00 2.88 748 424.60 4.37 749 424.60 4.54 750424.60 8.44 751 423.60 5.40 752 494.60 7.21 753 448.60 5.50 754 459.409.11 755 424.60 5.39 756 424.60 5.28 757 424.60 4.55 758 424.40 4.92 759495.40 10.29 760 422.00 2.66 761 475.00 2.95 762 475.00 2.95 763 462.002.94 764 429.00 2.76 765 443.00 2.67 766 457.00 3.03 767 443.00 1.75 768503.00 1.74 769 365.00 2.42 770 445.00 2.29 771 450.00 3.59 772 393.003.07 773 473.00 2.82 774 495.00 3.09 775 461.00 2.80 776 445.00 2.75 777445.00 2.76 778 471.20 2.78 779 471.20 2.82 780 471.00 2.80 781 471.002.78 782 458.00 2.87 783 441.00 2.90 784 445.00 2.79 785 427.00 2.69 786427.00 2.69 787 427.00 2.69 788 461.00 2.69 789 475.00 3.21 790 475.003.15 791 482.00 2.36 792 446.00 3.63 793 496.00 3.04 794 462.00 2.96 795448.00 2.84 796 446.00 2.84 797 462.00 2.98 798 496.00 3.11 799 432.002.75 800 430.00 1.82 801 457.00 2.60 802 444.00 2.70 803 448.00 2.73 804430.00 2.45 805 430.00 2.83 806 459.00 3.04 807 441.00 3.01 808 441.002.97 809 495.00 2.59 810 461.00 3.07 811 461.00 3.09 812 427.00 2.87 813424.40 4.83 814 522.00 2.32 815 488.00 1.49 816 452.00 2.62 817 461.002.84 818 441.00 3.08 819 463.00 2.96 820 429.00 2.10 821 445.00 2.77 822495.00 3.02 823 445.00 2.73 824 445.00 2.78 825 462.00 2.94 826 424.604.55 827 448.60 5.50 828 424.60 8.44 829 424.60 4.54 830 444.00 2.88 831449.00 2.70 832 452.00 2.50 833 495.00 3.00 834 447.00 2.41 835 445.002.70 836 445.00 2.70 837 429.00 2.76 838 461.00 2.84 839 461.00 2.80

Assays for Detecting and Measuring NaV Inhibition Properties ofCompounds

A) Optical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedsodium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the NaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with either a chemical or electrical means to evoke a NaVdependent membrane potential change from unblocked channels, which wasdetected and measured with trans-membrane potential-sensitive dyes.Antagonists were detected as a decreased membrane potential response tothe stimulus. The optical membrane potential assay utilizedvoltage-sensitive FRET sensors described by Gonzalez and Tsien (See,Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescenceresonance energy transfer in single cells” Biophys J 69(4): 1272-80, andGonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cellmembrane potential that use fluorescence resonance energy transfer” ChemBiol 4(4): 269-77) in combination with instrumentation for measuringfluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See,Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays andinstrumentation for screening ion-channel targets” Drug Discov Today4(9): 431-439).

B) VIPR® Optical Membrane Potential Assay Method with ChemicalStimulation

Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing aNaV1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coatedplates at 60,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest.

-   1) On the day of the assay, medium is aspirated and cells are washed    twice with 225 μL of Bath Solution #2 (BS#2).-   2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin    stock solution with 10% Pluronic 127 1:1 and then dissolving the mix    in the appropriate volume of BS#2.-   3) After bath solution is removed from the 96-well plates, the cells    are loaded with 80 μL of the CC2-DMPE solution. Plates are incubated    in the dark for 30 minutes at room temperature.-   4) While the cells are being stained with coumarin, a 15 μL oxonol    solution in BS#2 is prepared. In addition to DiSBAC₂(3), this    solution should contain 0.75 mM ABSC1 and 30 μL veratridine    (prepared from 10 mM EtOH stock, Sigma #V-5754).-   5) After 30 minutes, CC2-DMPE is removed and the cells are washed    twice with 225 μL of BS#2. As before, the residual volume should be    40 μL.-   6) Upon removing the bath, the cells are loaded with 80 μL of the    DiSBAC₂(3) solution, after which test compound, dissolved in DMSO,    is added to achieve the desired test concentration to each well from    the drug addition plate and mixed thoroughly. The volume in the well    should be roughly 121 μL. The cells are then incubated for 20-30    minutes.-   7) Once the incubation is complete, the cells are ready to be    assayed on VIPR® with a sodium addback protocol. 120 μL of Bath    solution #1 is added to stimulate the NaV dependent depolarization.    200 μL tetracaine was used as an antagonist positive control for    block of the NaV channel.

Analysis of VIPR® Data:

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu}{nm}} - {background}_{460\mspace{14mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu}{nm}} - {background}_{580\mspace{14mu}{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R..=R_(f)/R_(i) is thencalculated. For the Na⁺ addback analysis time windows, baseline is 2-7sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound

-   -   Solutions [mM]        Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10,        pH 7.4 with NaOH

-   Bath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂ 1, HEPES 10, pH 7.4    with KOH (final K concentration ˜5 mM)

-   CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at    −20° C.

-   DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C.

-   ABSC1: prepared as a 200 mM stock in distilled H₂O and stored at    room temperature

Cell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL#10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

C) VIPR® Optical Membrane Potential Assay Method with ElectricalStimulation

The following is an example of how NaV1.3 inhibition activity ismeasured using the optical membrane potential method#2. Other subtypesare performed in an analogous mode in a cell line expressing the NaV ofinterest.

HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO 10 mM DiSBAC₂(3)(Aurora #00-100-010) in dry DMSO 10 mM CC2-DMPE (Aurora #00-100-008) indry DMSO 200 mM ABSC1 in H₂O

Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented with 10mM HEPES (Gibco #15630-080)

Loading Protocol:

2× CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with anequivalent volume of 10% pluronic, followed by vortexing in requiredamount of HBSS containing 10 mM HEPES. Each cell plate will require 5 mLof 2× CC2-DMPE. 50 μL of 2× CC2-DMPE is to wells containing washedcells, resulting in a 10 μM final staining concentration. The cells arestained for 30 minutes in the dark at RT.

2× DISBAC₂(3) with ABSC1=6 μM DISBAC₂(3) and 1 mM ABSC1: The requiredamount of 10 mM DISBAC₂(3) is added to a 50 ml conical tube and mixedwith 1 μL 10% pluronic for each mL of solution to be made and vortexedtogether. Then HBSS/HEPES is added to make up 2× solution. Finally, theABSC1 is added.

The 2× DiSBAC₂(3) solution can be used to solvate compound plates. Notethat compound plates are made at 2× drug concentration. Wash stainedplate again, leaving residual volume of 50 μL. Add 50 uL/well of the 2×DiSBAC₂(3) w/ABSC1. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Reagents

Assay buffer #1

140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mMglucose, pH 7.40, 330 mOsm

Pluronic stock (1000×): 100 mg/mL pluronic 127 in dry DMSO

Oxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSO

Coumarin stock (1000×): 10 mM CC2-DMPE in dry DMSO

ABSC1 stock (400×): 200 mM ABSC1 in water

Assay Protocol

-   -   1. Insert or use electrodes into each well to be assayed.    -   2. Use the current-controlled amplifier to deliver stimulation        wave pulses for 3 s. Two seconds of pre-stimulus recording are        performed to obtain the un-stimulated intensities. Five seconds        of post-stimulation recording are performed to examine the        relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu}{nm}} - {background}_{460\mspace{14mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu}{nm}} - {background}_{580\mspace{14mu}{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R..=R_(f)/R_(i) is thencalculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound.

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

Voltage-Clamp Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (˜22° C.) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 MΩ.. using an Axopatch 200B amplifier(Axon Instruments). After establishing the whole-cell configuration,approximately 15 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated 60-70% and was monitored continuouslythroughout the experiment. The liquid junction potential (−7 mV) betweenthe intracellular pipette solution and the external recording solutionwas not accounted for in the data analysis. Test solutions were appliedto the cells with a gravity driven fast perfusion system (SF-77; WarnerInstruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +10 mV once every 60 seconds. Blockingeffects were allowed to plateau before proceeding to the next testconcentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA(1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33),KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3),glucose (5.6), HEPES (10), CdCl2 (0.4), NiCl2 (0.1), TTX (0.25×10⁻³).

Current-Clamp Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a Multiplamp700A amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filledwith (in mM):150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl₂,(buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140 NaCl,3 KCl, 1 MgCl, 1 CaCl, and 10 Hepes). Pipette potential was zeroedbefore seal formation; liquid junction potentials were not correctedduring acquisition. Recordings were made at room temperature.

Compounds of the invention as depicted generally herein and in Table 2were found to inhibit voltage-gated sodium channels at 25.0 μM or less.

Assays for Detecting and Measuring CaV Inhibition Properties ofCompounds

A) Optical Methods for Assaying CaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedcalcium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the CaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with electrical means to evoke a CaV dependent membranepotential change from unblocked channels, which was detected andmeasured with trans-membrane potential-sensitive dyes. Antagonists weredetected as a decreased membrane potential response to the stimulus. Theoptical membrane potential assay utilized voltage-sensitive FRET sensorsdescribed by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien(1995) “Voltage sensing by fluorescence resonance energy transfer insingle cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4(4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4(9): 431-439).

VIPR® optical membrane potential assay method with electricalstimulation

The following is an example of how CaV2.2 inhibition activity ismeasured using the optical membrane potential method. Other subtypes areperformed in an analogous mode in a cell line expressing the CaV ofinterest.

HEK293 cells stably expressing CaV2.2 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM Acid Yellow 17 (Aurora #VABSC) in H₂O

370 mM Barium Chloride (Sigma Cat# B6394) in H₂O

Bath X

160 mM NaCl (Sigma Cat# S-9888)

4.5 mM KCl (Sigma Cat# P-5405)

1 mM MgCl2 (Fluka Cat# 63064)

10 mM HEPES (Sigma Cat# H-4034)

pH 7.4 using NaOH

Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalentvolume of 10% pluronic, followed by vortexing in required amount of HBSScontaining 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE.50 μL of 2×CC2-DMPE is added to wells containing washed cells, resultingin a 10 μM final staining concentration. The cells are stained for 30minutes in the dark at RT.

2×CC2DMPE & DISBAC₆(3)=8 μM CC2DMPE & 2.5 μM DISBAC₆(3): Vortex togetherboth dyes with an equivalent volume of 10% pluronic (in DMSO). Vortex inrequired amount of Bath X with beta-cyclodextrin. Each 96 well cellplate will require 5 ml of 2×CC2DMPE. Wash plate with ELx405 with BathX, leaving a residual volume of 50 μL/well. Add 50 μL of 2× CC2DMPE &DISBAC₆(3) to each well. Stain for 30 minutes in the dark at RT.

1. 5×AY17=750 μM AY17 with 15 mM BaCl₂: Add Acid Yellow 17 to vesselcontaining Bath X. Mix well. Allow solution to sit for 10 minutes.Slowly mix in 370 mM BaCl₂. This solution can be used to solvatecompound plates. Note that compound plates are made at 1.5× drugconcentration and not the usual 2×. Wash CC2 stained plate, again,leaving residual volume of 50 μL. Add 100 uL/well of the AY17 solution.Stain for 15 minutes in the dark at RT. Run plate on the optical reader.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Assay Protocol

Insert or Use Electrodes into Each Well to be Assayed.

Use the current-controlled amplifier to deliver stimulation wave pulsesfor 3-5 s. Two seconds of pre-stimulus recording are performed to obtainthe un-stimulated intensities. Five seconds of post-stimulationrecording are performed to examine the relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu}{nm}} - {background}_{460\mspace{14mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu}{nm}} - {background}_{580\mspace{14mu}{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R..=R_(f)/R_(i) is thencalculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such asmibefradil, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound.

Electrophysiology Assays for CaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy of calciumchannel blockers expressed in HEK293 cells. HEK293 cells expressingCaV2.2 have been visually identified and probed with fine tip glasselectrodes connected to an amplifier (Axon Instruments). The “voltageclamp” mode has been used to assess the compound's IC50 holding thecells at −100 mV. The results of these experiments have contributed tothe definition of the efficacy profile of the compounds.

VOLTAGE-CLAMP assay in HEK293 cells expressing CaV2.2

CaV2.2 calcium currents were recorded from HEK293 cells using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (−22° C.) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 M. using an Axopatch 200B amplifier(Axon Instruments). After establishing the whole-cell configuration,approximately 15 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated 60-70% and was monitored continuouslythroughout the experiment. The liquid junction potential (−7 mV) betweenthe intracellular pipette solution and the external recording solutionwas not accounted for in the data analysis. Test solutions were appliedto the cells with a gravity driven fast perfusion system (SF-77; WarnerInstruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +20 mV for 50 ms at frequencies of 0.1,1, 5, 10, 15, and 20 Hz. Blocking effects were allowed to plateau beforeproceeding to the next test concentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA(1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), BaCl₂ (10), KCl (5.33),KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3),glucose (5.6), HEPES (10).

Following these procedures, representative compounds of the presentinvention were found to possess desired N-type calcium channelmodulation activity and selectivity.

In one embodiment, the present invention excludes compounds A-R below inTable X:

TABLE X Compound A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

1. A compound selected from the group consisting of 775

776

777

778

779

780

781

782

783

784

785

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

822

825

826

827

828

829

830

831

832

833

834

835

836

837

838


2. A pharmaceutical composition comprising a compound according to claim1, and a pharmaceutically acceptable adjuvant or carrier.